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AU2008229856A1 - Novel piperidines as chemokine modulators (CCR) - Google Patents

Novel piperidines as chemokine modulators (CCR) Download PDF

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Publication number
AU2008229856A1
AU2008229856A1 AU2008229856A AU2008229856A AU2008229856A1 AU 2008229856 A1 AU2008229856 A1 AU 2008229856A1 AU 2008229856 A AU2008229856 A AU 2008229856A AU 2008229856 A AU2008229856 A AU 2008229856A AU 2008229856 A1 AU2008229856 A1 AU 2008229856A1
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Australia
Prior art keywords
rhinitis
compound
oxo
formula
piperidin
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Abandoned
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AU2008229856A
Inventor
Lilian Alcaraz
Peter Cage
Mark Furber
Elizabeth Kinchin
Christopher Luckhurst
Aaron Rigby
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AstraZeneca AB
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AstraZeneca AB
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Priority to AU2008229856A priority Critical patent/AU2008229856A1/en
Publication of AU2008229856A1 publication Critical patent/AU2008229856A1/en
Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Description

P/00/0 1 Regulatioi 3.2
AUSTRALIA
Patents Act 1990 COMPLETE SPECIFICATION STANDARD PATENT Invention Title: Novel piperidines as chemokine modulators (CCR) The following statement is a full description of this invention, including the best method of performing it known to us: 00 IA 0 SNOVEL PIPERIDINES AS CHEMOKINE MODULATORS (CCR)
O
The present invention concerns piperidine derivatives having pharmaceutical activity, to processes for preparing such derivatives, to pharmaceutical compositions comprising such derivatives and to the use of such derivatives as active therapeutic agents.
t n Pharmaceutically active N-(2-hydroxyprop-l-yl)piperidine derivatives are disclosed in WO 03/068743.
o00 Histamineis a basic amine, 2-(4-imidazolyl)-ethylamine, and is formed from O histidine by histidine decarboxylase. It is found in most tissues of the body, but is present in high concentrations in the hmg, skin and in the gastrointestinal tract. At the cellular level inflammatory cells such as mast cells and basophils store large amounts of histamine.
It is recognised that the degranulation of mast cells and basophils and the subsequent release of histamine is a fundamental mechanism responsible for the clinical manifestation of an allergic process. Histamine producis its actions by an effect on specific histamine Gprotein coupled receptors, which are of three main types, HI, H2 and H3. Histamine H1 antagonists comprise the largest class of medications used in the treatment of patients with allergic disorders, for example rhinitis and urticaria. Antagonists of HI are useful in controlling the allergic response by for example blocking the action of histamine on postcapillary venule smooth muscle, resulting in decreased vascular permeability, exudation and oedema. The antagonists also produce blockade of the actions of histamine on the H1 receptors on c-type nociceptive nerve fibres, resulting in decreased itching and sneezing.
Chemokines are chemotactic cytokines that are released by a wide variety of cells to attract macrophages, T cells, eosinophils, baspliils and neutrophils to sites of inflammation and also play a role in the maturation of cells of the immune system.
Chemokines play an important role in immune and inflanmmatory responses in various diseases and disorders, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. These small secreted molecules are a growing superfamily of 8-14 kDa proteins characterised by a conserved four cysteine motif The chemokine superfamily can be divided into two main groups exhibiting characteristic structural motifs, the Cys-X-Cys or a) and Cys-Cys (C- C, or P) families. These are distinguished on the basis of a single amino acid insertion between the NH-proximal pair of cysteine residues and sequence similarity.
00 CN 2 SThe C-X-C chemokines include several potent chemoattractants and activators of
O
neutrophils such as interleukin-8 (IL-8) and neutrophil-activating peptide 2 (NAP-2).
O The C-C chemokines include potent chemoattractants of monocytes and lymphocytes, but not neutrophils, such as human monocyte chemotactic proteins 1-3 In 5 (MCP-1, MCP-2 and MCP-3), RANTES (Regulated on Activation, Normal T Expressed 00 and Secreted), eotaxins and the macrophage inflammatory proteins la and IP (MIP-l.
O and MIP-lp).
SStudies have demonstrated that the actions of the chemokines are mediated by subfamilies of G protein-coupled receptors, among which are the receptors designated CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CXCR1, CXCR2, CXCR3 and CXCR4. These receptors represent good targets for drug development since agents which modulate these receptors would be useful in the treatment ofdisorders and diseases such as fhose mentioned above.
Viral infections are known to cause lung inflammation. It has been shown experimentally that the common cold increases mucosal output of eotaxin in the airways.
Instillation of eotaxin into the nose can mimic some of the signs and symptoms of a common cold. (See, GreiffL et al Allergy (1999) L4(11) 1204-8 [Experimental common cold increase mucosal output of eotaxin in atopic individuals] and Kawaguchi M et al Int.
Arch. Allergy Immunol. (2000) 122 S1 44 [Expression of eotaxin by normal airway epithelial cells after virus A infection].) The compounds of the present invention are useful in the treatment of CCR3 mediated disease states (such as asthma and/or rhinitis) and show good specificity (for example 100-fold difference in activity) for the CCR3 receptor over other receptors present in a mammal such as G-Protein Coupled Receptors (for example: alpha 1 adrenoceptor and 5HT2B receptors) and ion channels (for example: the human ether-a-go-go-related gene (hERG) potassium channel).
The present invention provides a compound of formula OH 0 R O N-CH 2 CH2--N-LR3
(I)
H R wherein: R' is phenyl optionally substituted by halogen, cyano, CM4 alkyl or C.4 haloalkyl;
R
2 is hydrogen, CI-6 alkyl or C 36 cycloalkyl; and, 00 O R 3 is a group having an NH or OH that has a calculated or measured pKa of 1.0 to CO or a pharmaceutically acceptable salt.
o Certain compounds of the present invention can exist in different isomeric forms 0 (such as enantiomers, diastereomers, geometric isomers or tautomers). The present invention covers all such isomers and mixtures thereof in all proportions.
I Suitable salts include acid addition salts such as a hydrochloride, dihydrochloride, t hydrobromide, phosphate, sulfate, acetate, diacetate, fumarate, maleate, tartrate, citrate, c oxalate, methanesulfonate orp-toluenesulfonate. Salts.also include metal salts, such as an 00 alkali metal salt (for example a sodium or potassium salt) or an alkaline earth metal salt (for example magnesium or calcium).
The compounds of the invention may exist as solvates (such as hydrates) and the present invention covers all such solvates.
The pKa of a compound of formula is calculated using.4CD/Labs 6.00 software.
available from Advanced Chemistry Development Inc, 90 Adelaide Street, West Toronto, Ontario, Canada. The pKa of a compound of formula is measured using one of the methodologies recited below.
Halogen is, for example fluorine or chlorine.
Alkyl groups and moieties are straight or branched chain and are, for example, methyl, ethyl, n-propyl, iso-propyl or tert-butyL Cycloalkyl is monocyclic and is, for example, cyclopropyl, cyclopentyl or cyclohexyl.
Haloalkyl is an alkyl group carrying one or more (such as 1 to 6) halogen (such as chloro or fluoro atoms) and is, for example, CF 3
CH
2
CF
3 or C 2
F
5 Fluoroalkyl is an alkyl group carrying one or more (such as 1 to 6) fluoro atoms and is, for example, CH 2 F, CF3, CH 2
CF
3 or C 2 Fs.
In one aspect the present invention provides a compound of formula wherein R' is phenyl optionally substituted by halogen, cyano or Ci-4 alkyl.
In another aspect the present invention provides a compound of formula wherein R' is phenyl substituted with one, two or three of: halogen (such as fluoro or chloro), cyano or C-.
4 alkyl (such as methyl); for example R' is phenyl substituted by one, two or three of: fluoro, chloro, methyl or cyano. In another aspect R is phenyl substituted by one, two or three (such as two or three) of: fluoro, chloro, cyano or methyl (such as chloro, cyano or methyl). R' is, for example, 3,4-dichlorophenyl, 2-methyl-3-chloro-4-cyanophenyl, 2- 00 c-I 4
C.)
chloro-4-cyanopheflyl, 3,4-difluoropheflyl, 3-fluoro-4--chlorophenyl or 4-chiorophenyl 0(such as 2-methyl-4-chloropheflyl, 3-methyl-2,4-dichlorophelyL, 2-inethyl-3,4- INDdichiorophenyl, 3-chloro-4-cyanophenyl, 3,4-difluoropheflyl, 3-fluoro-4-chlorophenyl or 00 5 4-chiorophenyl). In a still further aspect R' is 3,4-dichiorophenyl or 3-ehloro-4cyanophenyl.
00I In a further aspect of the invention R' is phenyl substituted by one or more of chioro, or methyl and optionally further substituted by fluoro. For example is 2-methyl- 4-chiorophenyl, 3-methyl-2,4-diC111oropheflyl, 2-methyl-3,4-dichlorophenyl, 3-fluoro-4chiorophenyl, 4-chiorophenyl or 3,4-dichiorophenyl.
in another aspect of the invention R 1 is 3,4-dichiorophenyl, 2-niethyl-4-.
chiorophenyl, 3-methyl-2,4-dich1orophel, 2-methyl-3,4-dichlorophelyl or 2-methyl-3cbloro-4-cyanophelyl.
in a still further aspect the present inventibn provides a compound of forula (I) wherein R 2 is hydrogen or C 14 alkyl (such as methyl).
in yet another aspect of the invention R 2 is hydrogen.
The acidic NH (that is the NH having a calculated or measured pKa of 1.0 to of R 3 can be part of a ring or it can be part of a substituent on an aryl or heterocyclyl, ring.
The acidic OH (that is the OH having a calculated or measured pI~a of 1.0 to 8.0) of R 3 can be a substituent or part of a substituent (such an OH in a carboxylic acid group) on an aryl or heterocyclyl ring. Thus, for example, the acidic OH of RW can be part of an acidic phenol, in a carboxylic acid, or in a hydroxy aromatic heterocyclyl (such as a hydroxypyridifle which may tautomnerise to a pyridone).
Aryl includes optionally substituted phenyl and naphthyl.
Heterocyclyl is an optionally substituted aromatic or non-aromatic 5- or 6membered ring, comprising, as required, at least one heteroatom selected from the group compr ising nitrogen, oxygen and sulphur; or an N-oxide thereof, or an S-oxide or Sdioxide thereof. Heterocyclyl is, for example, furyl, thienyl (also known as thiophenyl), pyrrolyl, 2,5-dihydropyitolyl, thiazolyl (for example in 2-oxo-2,3-dihycdro-l,3-tbiazolyl), isothiazolyl, pyrazolyl, oxazolyl, isoxazolyl, iniidazolyl, triazolyl (for example in 1H- 1,2,3-triazolyl), pyridinyl (for example in 6-oxo-l,6-dihydro-pyridinyl) or pyrimidinyl.
In an aspect of the present invention the acidic NH of R? is part of a suitably substituted ring (for example part of a pyrrolyl, 2,5-dihydropyrrolyl, thiazoly], isothiazolyl, 005 pyrazolyl, oxazolyl, isoxazolyl, i-midazolyl, triazolyl, pyridiyl or pyrimidinyl ring) or part o of a substituent on a suitably substituted aryl (for example phenyl or naphthyl) or suitably o substituted heterocyclyl (for example furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, pyrazolyl, oxazolyl,.isoxazolyl, imidazolyl, triazolyl, pyridinyl or pyrimidinyl) ring.
kn in another aspect of the present invention the acidic OH of R 3 is a substituent or 00 part of a substitnent (such an OH in a carboxylic acid group) on a suitably substituted aryl cl (for example phenyl or naphthyl) or suitably substituted heterocyclyl (for example fury!,..
00 thienyl, pyrrolyl, 2,5-dihydropyrrolyl, thiazolyl, isothiazolyl, pyrazolyl, oxazolyl,.
N- 10 isoxazolyl, imidazolyl, triazolyl, pyridinyl or pyrimidinyl) ring. Thus, for example, the acidic OH of R 3 can be part of an acidic phenol (substituted or unsubstituited), in a* carboxylic acid, or in a suitably substituted hydroxy aromatic heterocyclyl (such as a hydroxypyridine which may tautomerise to a pyridone). Further examples of suitably substituted hydroxy'aromatic beterocyclyl are hydroxyqriinolines, hydroxyisoquinolines and hydroxybenzirnidazoles.
In one aspect of the present invention when the acidic NH of R 3 is part of a suitably substituted ring it is, for example, part of a 2 -oxo-thiazol-5-yl, 2 -oxo-oxazol-5-yl, 2-oxo- 1H-l,2,3-friazol-4-yl, 4-oxo- IH-1 ,4-diliydropyridin-3-yI, 2,6-dioxo-lH- S,2,3,6-tetrahydropyrimidin.4-yl, 6 -oxo-1H-1,6-dihydropyridin-3-y1 or ring.
In another aspect of the present invention when the acidic NH of W 3 is part of a suitably substituted ring it is, for example, part of a 2-oxo-thiazol-5-yl, lH-l,2,3-triazol-4yl or 6-oxo-lH-1,6-dihydropyridin-3-yl ring.
In a further aspect of the present invention when the acidic NH of is part of a substituent it is, for example, part of NHS(O) 2 (CJA4 alkyl).
In another aspect the present invention provides a compound of formula wherein R is a group having an NH or OH that has a calculated or measured pKa of 3 to In yet another aspect the present invention provides a compound of formula (I) wherein R is a group having an Nil or OH that has a calculated or measured pKa of 1.0 to 8.0 (for example 3 to the group R3 being, for example, having a suitable electron withdrawing substituent {suc:h as C 1 4 fluoroalkyl (for example CF 3
CH
2
CF
3 or C 2 17 5 an aryl group (for example 4- 00 c-I 6
C.)
alkyl)) in the A-position; having a suita ble electron withdrawing substituent {such as CI- IND fluoroalkyl (for example CF 3
CH
2
GF
3 or C 2 1F 5 or CH2S(O) 2
(C
1 4 alkyl)} in the 4tn5 position;, 00 c-i H-l,2,3-triazol-4-yl having a suitable substituent (such as C 14 alkyl (for example 00
CH
3 or CH(C11 3 2 C3. cycloalkyl (for example cyclopropyl), 01-4 iluoroalkyl (for example CF3, CH 2
GF
3 or C 2 Fs), S-R 4 (wherein 1( is CIA alkyl [for example CH 3 CI-4 fluoroalicl [for example CF 3 CHiCF 3 or C 2 Fs] or C3.
6 cycloalkyl [for example cYcloproPYlD, NHS(0) 2 (Ci- 4 Akyl), N(C 1 4 alkYl)S(0)2(C, 4 alkyl), an arYl group (for example 4-finorophenyl), a heterocyclyl group (for example pyridyl) or a group CH 2 S(0) 2 (C14~ alcYl)) in the 9 4-oxo-lH-l,4-diydropyridin-3-yl having a suitable electron withdrawing sub stituent (such as 01.4 fluoroalicyl (for example CF 3 of C,2Fs)} in the2-otin 2,6-dioxo-lH-l,2,3,6-tetrahydropyrimidin-4-yI having a suitable substituent {such as C 1 4 alcyl (for example 0113), C3. cycloalkyl (for example cyclopropyl) or
CHAP(C
1 3 fluoroakl) (for example CIHzCF 3 in the 3-position and optionally substituted in one or more other ring positions; 6-oxo-lH-l,6-dihydropyridin-3-yl having a suitable electron withdrawing substituent {such as C 14 fluoroalkyl (for example CF 3
CH
2
CF
3 or C 2 Fs), cyano, or phenyl} in the 2-position and/or the 5-position and optionally substituted in one or more other ring positions; 6-oxo-lH-1,6-dihydropyridin-3-yl having CH 2
CO
2 H on the ring nitrogen and optionally substituted in one or more other ring positions; a C0214, CH 2
CO
2 H or OCH 2
CO
2 H group on an optionally substituted phenyl, optionally substituted CH 2 Ophenyl,- optionally substituted naphtbyl ring or optionally substituted acylated (such as with C(0)(Cl.4 alkyl)) dihydroisoquinolinyl ring; or, .an N[IS(0) 2 (CI-4 alkyl) (for example NI{S(O) 2
CH
3 group on an optionally substituted aromatic heterocyclyl ring (for example pyridinyl, pyrimidinyl or thiazolyl); or, where possible, a tautomner thereof.
00 7 In one aspect of the invention acylated (such as with 4 alkyl)) dihydroisoquinolinyl carries thie CO 2 H, CH 2
CO
2 H or OCH 2
CO
2 H group on position 7.
0 In yet another aspect the present invention provides a compound of formula (1) wherein R. is a group having an NH or OH -that has a calculated or measured pKa. of 1.0 to 8.0 (for example 3 to the group RY being, for example, IND* 2-oxo-thiazol-5-yI having a suitable electron withdrawing substituent {such as C 1 -4 00 00 fluoroalkyl (for example CE 3
CII
2
CF
3 or C 2 Fs), an aryl group (for example 4c-ifluorophenyl), a heterocyclyl group (for example pyridyl) or a group CH 2
S(O)
2
(C
1 4 00 alkyl)) in the 4-p osition; N- 10 *2-oxo-oxazol-5-yl having a suitable electron withdrawing substituent {such as C 14 fluoroalk (for example CE 3
CH
2
CF
3 or C 2 Fs) or CH 2
S(O)
2
(C
1 4 alkl)} in the 4position; lH-1,2,3-triazol-4-yl having a suitable substituent. {such bas C 1 alkyl (for example
CH
3
C
3 6 cycloalkyl (for example cyclopropyl), CI_ 4 fluo~roalkyl (for example CF 3
CH
2
CF
3 or Cz2F 5
S-R
4 (wherein le~ is C 14 alkyl [for example CH 3
CI-
4 fluoroakl [for example CF 3
CH
2
CF
3 or C 2 F5] or C 3 6 cyclOalkyl [for example cyclopropyl]), NHS(O) 2 (Ci- 4 alkyl), an aryl. group (for example 4-fluorophenyl), a heterocyclyl. group (for example pyridyl) or a group CH 2 S (0) 2
(C,
4 alkyl)) in the position; 4-oxo-IH-l,4-dihydropyridin-3-yl having a suitable electron withdrawing substituent. {such as C 1 fluoroalkyl (for example CF 3 of C2jFs)} in the 2-position; 2,6-dioxo-1E-l ,2,3,6-tetrahydropyrimidin-4-yI having a suitable substituent {such as CI_4 ailkyl (for example CH 3
C
3 6 cycloallcyl (for example cyclopropyl) or
CH
2
(CI.
3 fluoroalkyl) (for example CH 2
CF
3 in the 3-position; 0 6-oxo-lH-l,6-dihydropyridin-3-yl having a suitable electron withdrawing substituent (such as C 14 fluoroalkyl (for example CF 3
CH
2
CF
3 or C 2 Fs) or cyano} in the 2-position or the 5-position and optionally substituted in other positions; a C0 2 H group on an optionally substituted phenyl or naphthyl ring; or, an iNHS(O) 2
(C
1 4 alkyl) (for example NHS(O) 2
CH
3 group on an optionally substituted aromatic heterocyclyl ring (for example pyridinyl, pyrimidinyl or thiazolyl); or, where possible, a tautomer thereof.
00 c-I 8
C.)
it can be optionally substituted by, for example: fluoro, chioro, bromo, C14 alkyl (for example methyl), C 3 6 cycloalkyl (for example cyclopropyl), CI-4 fluoroalkyl (for example
INDCF
3
CH
2
CF
3 or C 2 Fs), S-F.
4 (wherein I( is C 1 4. alkyl [for example OH 3 CI- fluoroalkyl 00 5 [for example CE 3
CH
2 CF3 or C 2
F
5 or C 3 6 cycloalkyl [for example cyclopropyl]), cyano, N S(0) 2
(C
14 alkyl) (for example S(O) 2
CH
3 Or S(0) 2
NH(C
1 4 alkyl) (for example 00 S(O)jNHCH 3 Where indicated above that a phenyl or naphthyl ring in F.
3 may be optionally substituted it can be optionally substituted by, for example, halogen, cyano, C 1 4 alkYl, C 1 -4 alkoxy, C 1 4 fluoroakyl (for example CF 3
CH
2
CF
3 Or C 2
F
5
OCF
3
SCF
3 nitro, S(C.4 alkyl), S(O)(CIA alkyl), S(O) 2
(C
14 alkyl), S(O) 2
NH(C]
4 alkyl), S(0) 2
N(C
14 alkyl) 2 In one aspect of the invention R 3 is having CI-4fluoroalkyl (for example CE 3
CH
2
CF
3 or C7F5) in the 4-position; 1H-l,2,3-triazol-4-yl having a suitable substituent (such as CIA4 alkYl (for example
CH
3 or S-R 4 (wherein Re is C 1 4 fluoroalcyl [for example CE 3
CH
2
CF
3 or C 2 Fs])) in the 0 2,6-dioxo-IH-l ,2,3,6-tetrahydropyrimidin-4-yl having a suitable substituent {such as alkyl (for example CH 3 or C 1 4 fluoroalkyl (for example CF 3
CH
2
CF
3 or
C
2
F
5 in the 3-position; 0 6-oxo-lH-l,6-dihydropyridifl-3-yl having a suitable electron withdrawing substituent (such as C 1 4 fluoroalk (for example OF 3
CH
2
CF
3 or C 2 Fs) or cyano} in the 2-position or the 5-position and optionally substituted in other positions; a C0 2 H group on an optionally substituted napbthyl ring; or, an NHS(O) 2
(C
1 4 alkyl) (for example NHS(O) 2
CH
3 group on an optionally substituted aromatic heterocyclyl ring (for example pyridinyl, pyrimidinyl or thiazolyl); or, where possible, a tautomer thereof; the optional substituents being as defined above.
In yet another aspect the present invention provides a compound of fortmula (1) wherein R 3 is: 00 c-I* 9 having a suitable electron withdrawing substituent (such as C 1 -4 fluoroalcyl (for example CE 3
CH
2
CF
3 or C 2 FS), a phenyl group (for example 4fluorophenyl) or a heterocyclyl group (for example pyridyl)} in the 4-position; IND lH-l,2,3-triazol-4-yl having a suitable substituent {such as CIA 4 alkl (for example in 5 CH 3 or CII(CH 3 2 CI-4 fluoroalkyl (for example CE 3 CH1 2
CF
3 or C 2
F
5
S-R
4 (wherein e 4 is C1. alkyl [for example CH 3 or C1.
4 fluoroalcyl [for example CE 3 00 CH 2
CF
3 or C 2 N(Cj.4 alkyl)S(O) 2
(C
1 4 alkyl) or a phenyl group (for example 4fluorophenyl)} in the-5-position; or, *6-oxo-lH-l,6-dihydropyridin-3-yl having Cl.: fluoroallcyl (for example CF 3
CH
2
CF
3 or C 2
E
5 or cyano in the 2-position or the .ii another aspect the present invention provides a compound of formula wherein R is: e 2-oxo-thiazol-5-yl having CF 3 or C 2 Fs in the 4-position; e IH-1,2,3-triazol-4-yl having CF 3
C
2 Fs, SCF 3
SCH
2
CF
3 or SC 2
F
5 (for example CF 3 or SCH 2
CF
3 in the 5-position; or, *6-oxo-1H-l,6-dihydropyridin-3-yl having CF 3 or C 2
F
5 in the 2-position.
In yet another aspect the present invention provides a compound of formula (I) wherein the 2-hydroxy group has the stereochemistry shown below: HO, H 0 Compounds of the invention are illustrated in the Examples below.
Compounds of the present invention can be prepared by methods described, or analogous to those described, in the art (for example WO 031068743). Intermediates for such processes can be prepared by methods described, or analogous to those described, in -the art (for example WO 03/068743).
A compound of formula can be prepared by reacting a compound of formula
(II):
R O" N CH--r-CH- 2 NH (11) H R wherein R' and R3 are as defined above, with a compound of formula (III): 00 0 wherein L' is a leaving group (for example a hydroxy or chioro leaving group), and R? is IND as defined above; in the presence of a base (for example a tri(Cl-6 alkyl)anaine base (such kn as triethylamine or diisopropylethylamine) or NN-dimethylformamide), in the presence of 00 a suitable solvent (for example N-dimethyformamide, tetrahydrofuran, dichioromethane 00 or dioxane, or a mixture of one or more of these solvents) optionally in the presence of a coupling agent (for example bromo-tris-pynrolidinophosphonium liexafluorophosphate, PyBrOP or O{(7-azabenzotriazol-1 -yl)-NNN',N'tetramethyluronu hexafluorophosphate).
A compound of formula (11) can be prepared as described in WO 00/58305 or WO 01/710 1, or by reacting a compound of formula (WV): R O (IV) wherein R 1 is defined above, with: a compound of formula MV: 0
L-CH
2 O H 2
MV
H-
in which L 2 is a leaving group (for example chioro or nosyloxy {3-NO 2 -C6Ji 4
-S(O)
2 0-) followed by reaction with ammonia, an amine l( 2 -NH4 2 or with sodium azide and subsequent reduction with, for example, triphenylphosphine; or, (ii) with a compound of formula (VI): 0
CH
2
CH
2
NPIP
2
(VI)
H
in which P1 and P 2 are, alone or together, suitable protective groups (for example together they form phthalimide), or either P' or 1p 2 is B.
2 followed by deprotection using, for example when P1 and P 2 form phthalimide, hydirazine.
A compound of formula can be obtained commercially or can be prepared using methods described in the literature.
00
O
(C 11 o A compound of formula (VI) can be prepared by reacting or glycidol under 0Mitsunobu reaction conditions with, for example, phthalimide, 1,1-(azodicarbonyl) dipiperidine and tributylphosphine (Tetrahedron Lett. 1993, 34, 1639).
D Further, a compound of formula can be prepared by routine adaptation of: the 00 5 routes described above, methods described in the art, or the Examples recited below. The .1 intermediates identified above are commercially available or can be prepared by using or 00 adapting methods described in the art.
0 In another aspect the present invention provides processes for the preparation of compounds of formula The compounds of the invention have activity as pharmaceuticals, in particular as modulators of chemokine receptor (for example CCR3) activity, and may be used in the treatment of autoimmune, inflammatory, proliferative or hyperproliferative diseases, or immunologically-mediated diseases (including rejection of transplanted organs or tissues and Acquired Immunodeficiency Syndrome (AIDS)).
In one aspect examples of these conditions are: (the respiratory tract) obstructive diseases of airways including: chronic obstructive pulmonary disease (COPD) (such as irreversible COPD); asthma {such as bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma (for example late asthma or airways hyper-responsiveness)}; bronchitis (such as eosinophilic bronchitis); acute, allergic, atrophic rhinitis or chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous or pseudomembranous rhinitis or scrofulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) or vasomotor rhinitis; sarcoidosis; farmer's lung and related diseases; nasal polyposis; fibroid lung, idiopathic interstitial pneumonia, antitussive activity, treatment of chronic cough associated with inflammatory conditions of the airways or iatrogenic induced cough; (bone and joints) arthrides including rheumatic, infectious, autoimmune, seronegative spondyloarthropathies (such as ankylosing spondylitis, psoriatic arthritis or Reiter's disease), Behget's disease, Sjogren's syndrome or systemic sclerosis; (skin and eyes) psoriasis, atopic dermatitis, contact dermatitis or other eczmatous dermitides, seborrhoetic dermatitis, Lichen planus, Phemphigus, bullous Phemphigus, 00 C- 12 O Epidermolysis bullosa, urticaria, angiodermas, vasculitides erythemas, cutaneous
O
Seosinophilias, uveitis, Alopecia areata or vernal conjunctivitis; O (gastrointestinal tract) Coeliac disease, proctitis, eosinophilic gastro-enteritis, mastocytosis, Crohn's disease, ulcerative colitis, irritable bowel disease or foodn 5 related allergies which have effects remote from the gut (for example migraine, 00 rhinitis or eczema); 00 (Allograft rejection) acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea; or chronic graft versus host disease; and/or (other tissues or diseases) Alzheimer's disease, multiple sclerosis, atherosclerosis, Acquired Immunodeficiency Syndrome (AIDS), Lupus disorders (such as lupus erythematosus or systemic lupus), erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, leprosy (such as lepromatous leprosy), Peridontal disease, Sezary syndrome, idiopathic thrombocytopenia pupura or disorders of the menstrual cycle.
The compounds of the invention are also H1 antagonists and maybe used in the treatment of allergic disorders.
The compounds of the invention may also be used to control a sign and/or symptom of what is commonly referred to as a cold (for example a sign and/or symptom of a common cold or influenza or other associated respiratory virus infection).
According to a further feature of the invention there is provided a compound of formula or a pharmaceutically acceptable salt thereof, for use in a method of treatment of a warm blooded animal (such as man) by therapy (including prophylaxis).
According to a further feature of the present invention there is provided a method for modulating chemokine receptor activity (for example CCR3 receptor activity), or antagonising HI, in a warm blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound of the formula or a pharmaceutically acceptable salt thereof.
The invention also provides a compound of the formula or a pharmaceutically 0 acceptable salt thereof, for use as a medicament.
In another aspect the invention provides the use of a compound of formula or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in 00
O
O
N 13 o therapy (for example modulating chemokine receptor activity (for example CCR3 receptor activity), or antagonising HI, in a warm blooded animal, such as man).
The invention further provides the use of a compound of formula or a N pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the V) 5 treatment of: 00 I (the respiratory tract) obstructive diseases of airways including: chronic obstructive 00 pulmonary disease (COPD) (such as irreversible COPD); asthma {such as bronchial, Sallergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma (for example late asthma or airways hyper-responsiveness)}; bronchitis {such as eosinophilic bronchitis}; acute, allergic, atrophic rhinitis or chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous or pseudomembranous rhinitis or scrofulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) or vasomotor rhinitis; sarcoidosis; farmer's lung and related diseases; nasal polyposis; fibroid lung, idiopathic interstitial pneumonia, antitussive activity, treatment of chronic cough associated with inflammatory conditions of the airways or iatrogenic induced cough; (bone and joints) arthrides including rheumatic, infectious, autoimmune, seronegative spondyloarthropathies (such as ankylosing spondylitis, psoriatic arthritis or Reiter's disease), Beh9et's disease, Sjogren's syndrome or systemic sclerosis; (skin and eyes) psoriasis, atopic dermatitis, contact dermatitis or other eczmatous dermitides, seborrhoetic dermatitis, Lichen planus, Phemphigus, bullous Phemphigus, Epidermolysis bullosa, urticaria, angiodermas, vasculitides erythemas, cutaneous eosinophilias, uieitis, Alopecia areata or vernal conjunctivitis; (gastrointestinal tract) Coeliac disease, proctitis, eosinophilic gastro-enteritis, mastocytosis, Crohn's disease, ulcerative colitis, irritable bowel disease or foodrelated allergies which have effects remote from the gut (for example migraine, rhinitis or eczema); (Allograft rejection) acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea; or chronic graft versus host disease; and/or (other tissues or diseases) Alzheimer's disease, multiple sclerosis, atherosclerosis, Acquired Immunodeficiency Syndrome (AIDS), Lupus disorders (such as lupus 00 N 14 o erythematosus or systemic lupus), erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, leprosy (such as lepromatous leprosy), Peridontal disease, sezary syndrome, idiopathic thrombocytopenia pupura or disorders of the menstrual cycle; 00 5 in a warm blooded animal, such as man.
In a further aspect a compound of formula or a pharmaceutically acceptable salt 0o thereof, is useful in the treatment of asthma {such as bronchial, allergic, intrinsic, extrinsic Sor dust asthma, particularly chronic or inveterate asthma (for example late asthma or airways hyper-responsiveness)}; or rhinitis {including acute, allergic, atrophic or chronic rhinitis, such as rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous or pseudomembranous rhinitis or scrofulous rhinitis; seasonal rhinitis including rhinitis nervosa. (hay fever) or vasomotor rhinitis}. In a still further aspect a compound of formula or a pharmaceutically acceptable: salt thereof, is useful in the treatment of asthma.
The present invention also provides the use of a compound of formula or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of asthma or rhinitis.
The present invention further provides a method of treating a chemokine mediated disease state (for example a CCR3 mediated disease state, such as asthma) in a warm blooded animal, such as man, which comprises administering to a mammal in need of such treatment an effective amount of a compound of formula or a pharmaceutically acceptable salt thereof.
In order to use a compound of the invention, or a pharmaceutically acceptable salt thereof, for the therapeutic treatment of a warm blooded animal, such as man, in particular modulating chemokine receptor (for example CCR3 receptor) activity or antagonising H1, said ingredient is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
Therefore in another aspect the present invention provides a pharmaceutical composition which comprises a compound of the formula or a pharmaceutically acceptable salt thereof (active ingredient), and a pharmaceutically acceptable adjuvant, diluent or carrier. In a further aspect the present invention provides a process for the preparation of said composition which comprises mixing active ingredient with a 00 pharmaceutically acceptable adjuvant, diluent or carrier. Depending on the mode of administration, the pharmaceutical composition will, for example, comprise from 0.05 to 99%/w (per cent by weight), such as ftrm 0.05 to 80%w, for example from 0. 10 to INO such as from 0. 10 to 500%w, of active ingredient, all percentages by weight being based on V) 5 total composition.
00 The pharmaceutical compositions of this invention may be administered in standard 00 manner for the disease condition that it is desired to treat, for example by topical (such as 0 to the lung and/or airways or to the skin), oral, rectal. or parenteral administration. For these purposes the compounds of this invention may be formulated by means known in the art into the form of, for example, aerosols, dry powder formulations, tablets, capsules, syrups, powders, granules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, ointments, creams, drops and sterile injectable aqueous or oily solutions or suspensions.
A suitable pharmaceutical composition of this invention is-one suitable for oral administration in unit dosage form, for example a tablet or capsule which contains between 0. 1mg and I g of active ingredient.
In another aspect a pharmaceutical composition of the invention is one suitable for intravenous, subcutaneous or intramuscular injection.
Each patient may receive, for example, an intravenous, subcutaneous or intramuscular dose of 0.01 mgkg-1 to 100 mgkg 1 of the compound, for example in the range of 0. 1 mgkg' to 20 mgkg7' of this invention, the composition being administered 1 to 4 times per day. The intravenous, subcutaneous and intramuscular dose may be given by means of a bolus injection. Alternatively the intravenous dose may be given by continuous infusion over a period of time. Alternatively each patient will receive a daily oral dose which is approximately equivalent to the daily parenteral dose, the composition being administered 1 to 4 times per day.
The invention further relates to combination therapies or compositions wherein a compound of formula or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula or a pharmaceutically acceptable salt thereof, is administered concurrently (possibly in the same composition) or sequentially with an agent for the treatment of any one of the above disease states.
In particular, for the treatment of the inflammatory diseases rheumatoid arthritis, psoriasis, inflammatory bowel disease, COPD, asthma and allergic rhinitis a compound of 00 Cl 16 o the invention can be combined with a- TNF-z. inhibitor (such as an anti-TNF monoclonal antibody (such as Remicade, CDP-870 and D.sub2.E.sub7.),!or a TNF receptor immunoglobulin molecule (such as Enbrel.reg.)), a non-selective COX-1 COX-2 inhibitor IND (such as piroxicam or diclofenac; a propionic acid such as naproxen, flubiprofen, V) 5 fenoprofen, ketoprofen or ibuprofen; a fenamate such as mefenamic acid,. indomethacin, 00 sulincac or apazone; a pyrazolone such as phenylbutazone; or a salicylate such as aspirin), 00 a COX-2 inhibitor (such as meloxicam, celecoxib, rofecoxib, valdecoxib or etoricoxib) low dose metbotrexate, lefunon de; ciclesonide; hydroxychioroquine, d-penicillanine or c-I auranofin, or parenteral or oral gold.
The present invention still further relates to the combination of a compound of the invention together with: *a leukotriene biosynthesis inhibitor, a 5-lipoxygenase (5-LO) inhibitor or a lipoxygenase activating protein (FLAP) antagonist, such as zileuton, ABT-761, fenleuton, tepoxalin, Abbott-79 175, Abbott-85761, an 2-allkylsulfonamide, a 2,6-di-tert-butyiphenol hydrazones, a methoxytetalydropyran such as Zeneca ZD-213 8, SB-21066 1, a pyridinylsubstituted 2-cyanonaphthalene compound such as L,739,010; a 2-cyanoquinoline compound such as L-746,530; an indole or quinoline compound such as MK-591, MK-886 or BAY x 1005; e a receptor antagonist for a leukotriene LTB.sub4., LTC.sub4., LTD.sub4. or LTE.sub4. selected from the group consisting of a phenothiazin-3-one such as L- 1,392; an amidino compound such as CGS-25019c; a benzoxalamine such as ontazolast; a benzenecarboximidamide such as BIEL 284/260; or a compound such as zafirlulcast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP 45715SA) or BAY x 7195; a PDE4 inhibitor including an inhiibitor of the isoform PDE4D; an antihistamninic H.sub I. receptor antagonist such as cetirizine, loratadine, desloratadine, fexofenadine, astemnizole, azelastine or chiorpheniramine; a gastroprotective E.sub2. receptor antagonist; an ct.sub and a.sub2.-adrenoceptor agonist vasoconstrictor sympathomimetic agent, such as propyihexedrine, pbenylephrine, phenylipropanolamine, pseudoephedrine, naphiazoline hydrochloride, oxymetazoline hydrochloride, 00 17 tetrahydrozoline hydrochloride, xylometazoline hydrochloride or o ethylnorepinephrine hydrochloride; *an anticholinergic agent such as ipratropiumn bromide, tiotropium. bromide, oxitropiumn bromide, pirenzepine or telenzepine; 5a f.subl.- to P.sub.-adrenoceptor agonist such as metaproterenol, isoproterenol, 00 isoprenaline, albuterol, salbutamol, formoterol,, saitneterol, terbutaline, orciprenaline, bitolterol niesylate or pirbuterol, or a tuethyixanthanine including 00 theophylline and aminophylline; sodium cromoglycate; or a muscarinic receptor (M I, Nn, and M3) antagonist; 0 an insuliii-Iilke growth factor type I (1GB-I) mimetic; an inhaled glucocorticoid with reduced systemic side effects, such as prednisone, prednisolone, fhxnisolide, triameinolone acetonide, beclomethasone dipropionate, budesonide, fluticisone propi6nate or mometasone furoate; o an inhibitor of a matrix metalloprotease (IVMW), such as a stromelysin, a collagenase, or a gelatinase or aggrecanase; such as collagenase-1 (IvMP-1), collagenase-2 collagenase-3 (MMP-13), stromelysi-1 (MWvI-3), stromelysin-2 WMM-10), and stromelysin-3 (MMvP-1 1) orMMP-12; 9 a modulator of chemokine receptor funaction. such as CCRI, CCR2, CCR2A, CCR2B, CCR3, CCR,4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR1O0 and CCRI 1 (for the C-C family); CXCRI, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C- X-C family) and CX 3 CRI for the C-X 3 -C family; an osteoporosis agent such as roloxifene, droloxifene, lasofoxifene or fosoinax; 0 an immunosuppressant agent such as FK-506, rapamycin, cyclosporine, azathioprine or methotrexate; a compound useful in the treatment of AIDS and/or HIV infection for example: an agent which prevents or inhibits the viral protein gpl120 from engaging host cell CD4 {such as soluble CD4 (recombinant); an anti-CD4 antibody (or modified/ recombinant antibody) for example PR0542; an anti-group 120 antibody (or modified recombinant antibody); or another agent which interferes with the binding of groupl20 to CD4 for example BMS8O6}; an agent which prevents binding to a chemokine receptor, other than CCR5, used by the HIV virus (such as a CXCR4 agonist or antagonist or an anti-CXCR4 antibody); a compound which interferes in the fusion between the HIV viral envelope and a cell membrane {such 00 c-i 18 o as an anti-group 41 antibody; enfuvirtide (T-20) or T-1249}; an inhibitor of DC- SIGN (also known as CD209.) {such as an anti-DC-SIGN antibody or an inhibitor of DC-SIGN binding); a nucleoside/nucleotide analogue reverse transciptase INDinhibitor (for example zidovudine (AZT), nevirapine, didanosine zalcitabine 5 (ddC), stavudine (d4T), lamivudine abacavir, adefovir or tenofovir (for 00 example as free base or as disoproxil fumnarate)) a non-nucleoside reverse 00transciptase -inhibitor (for example nevirapine, delavirdmne or efavirenz}); a protease inhibitor {for example ritonavir, indinavir, saquinavir (for example as free base or c-I *as~mesylate salt), nelfinavir (for example as free base or as mesylate salt), amprenavir, lopinavir or atazanavir (for example as free base or as sulphate salt)); a ribonucleotide reductase inhinbitor {for example hydroxyurea}; or an antiretroviral {for example emtricitabine}; or, *an-existing therapeutic agent for the treatment of osteoarthritis, for example a nonsteroidal anti-inflammatory agent (hereinafter NSAIID's) such as piroxicamn or diclofenac, a propionic acid such as naproxen, f lubiprofen, fenoprofen, ketoprofen or ibuprofen, a fenamate such as mefenamic acid, indomethacin, sulindac or apazone, a pyrazolone such as phenylbutazone, a salicylate such as aspirin; a COX- 2 inhibitor such as celecoxib, valdecoxib, rofecoxib or etoricoxib, an analgesic or intra-articular therapy such as a corticosteroid or a hyaluronie acid such as hyalgaii or synvisc, or a P2X7 receptor antagonist.
11e present invention still fur-ther relates to the combination of a compound of the invention together with: a tryptase inhibitor; (ii) a platelet activating factor(P antagonist (iii) an interleukin converting enzyme (ICE) inhibitor; (iv) an IMPDH inhibitor; an adhesion molecule inhibitor including a VLA-4 antagonist;, (vi) a cathepsin; (vii) a MAP kinase inhibitor; (viii) a glucose-6 phosphate dehydrogenase inhibitor; (ix) a kinin-B.subl. and B.sub2. -receptor antagonist; an anti-gout agent, coichicine; (xi) a xantbine oxidase inhibitor, allopurinol; (xii) an uricosuric agent, probenecid, sulfinpyrazone or benzbromarone; (xiii) a growth hormone secretagogue; (xiv) a transforming growth factor (TGFI3); (xv) a platelet-derived growth factor (PDGF); (xvi) a fibroblast growth factor, basic fibroblast growvth factor (bFGF); (xvii) a granulocyte macrophage colony stimulating factor (GM-.CSF); (xviii) a capsaicin .cream; (xix) a Tachykinin NK.subl.- and NK.sub3. receptor antagonist selected from the group consisting of NKP-608C; SIB-233412 (talnetant); and D-4418; (xx) an elastase inhibitors 00
O
O
CM 19 o selected from the group consisting of UT-77 and ZD-0892; (xxi) a TNFa converting enzyme inhibitor (TACE); (xxii) an induced nitric oxide synthase inhibitor (iNOS); or
O
(xxiii) a chemoattractant receptor-homologous molecule expressed on TH2 cells (a CRTH2 \0 antagonist).
tn 00 CI The pKa of a compound of formula is measured using one of the following 00 methodologies.
SMethod A The apparatus used consists of a Sirius GLpKe instrument with DPAS (Dip Probe Absorption Spectroscopy) attachment. Key elements of the apparatus are a Sirius pH electrode, stirrer, titrant dispensing tubes, a multi-tipped dispenser, motor driven dispensing syringes, fibre optic UV probe and diode array detector. In addition, solutions in PTFE containers of ionic strength adjusted (0.10M KC1) distilled water, nominally 0.50 M HC1, nominally 0.50 M KOH and 80% v/v methanol:water are also housed within the instrument The titration solutions are constantly purged with oxygen free nitrogen. The reservoir for the potassium hydroxide solution is further protected from atmospheric contamination by a soda-lime guard-tube. Samples are placed in titration vessels which in turn are placed in a movable autosampler tray (maximum capacity 48 samples). The electrode, stirrer, dispensing tubing/tips and DPAS probe are housed on a movable, automated z-tower unit, which, controlled by software, positions itself in the appropriate titration vessel when titrating. The Sirius GLpK, instrument is directly connected to a dedicated PC supporting software for assay setup and subsequent data analysis. Assays are set up using the GlpKaControl software and results are analysed using the pKaLOGP and pKaUV software on the PC. The software also allows determination of multiple pKas using complex curve fitting analyses.
Method B: Potentiometric Method Two types ofpotentiometric titrations may be performed in order to determine a compound's pKa/pKs; a purely aqueous titration (recommended for fairly water soluble compounds) and a cosolvent titration, where variable amounts of methanol are added to the sample in addition to ionic strength adjusted water (recommended for compounds which are not soluble in water). For the latter, a value for the compound's pKa in pure ionic strength adjusted water can be estimated by the Yasuda-Shedlovsky procedure. This 00 CN- 0 involves measuring the apparent pKa of the compound at three known weight percentages
O
of methanol:water (transposed into reciprocals of the dielectric constants of the medium, O 1/sr) and then extrapolating to 0 wt%/ methanol (1/s 1.282 x 103).
I The GLpK, instrument unit also houses two aqueous wash containers (containing n 5 distilled water), a waste beaker (to dispense extraneous solutions into) and a container i holding pH 7.00 buffer solution for the electrode to be immersed in during periods between 00 titrations. Each time a set of titrations is carried out, these solutions are replaced. Position S1 in the autosampler contains a titration vessel containing pH 7.00 buffer solution (changed for each titration set). For each titration set to be run, position 2 houses a titration vessel into which ionic strength adjusted water is dispensed (typically 15.00 mL). This in turn is adjusted to pH 1.80 with aqueous HCI and then titrated to pH 12.20 by gradual addition of aqueous KOH. This is referred to as a blank titration and is employed by the pKaLogP software in order to calibrate the pH electrode and to standardise the HC1 solution, using the so-called four-plus parameter procedure. Periodically, (typically every 3 months, or when the titration solutions run low) the titration solutions are replaced and the KOH solution standardised against potassium hydrogen phthalate using a standardisation procedure within the GLpKaControl software. Between 1-2 mg of each sample must be accurately weighed out. Samples are placed in provided glass titration vessels. The weight of compound must be entered into the GLpKaControl software. Other parameters that need to be entered are; the molecular weight of the compound, assay type (aqueous, cosolvent), number of assays in the beaker (1 for aqueous titrations, 3 for cosolvent/mixed solvent titrations), formula (eg. X for a compound not present as a salt, or XHCI for a compound introduced as a hydrochloride salt), expected number ofpKas (from known structure), minimum pH (1.80 for operational minimum of electrode), maximum pH (12.20 for operational maximum of electrode), first assay direction (low to high pH recommended for bases, high to low pH recommended for acids), starting aqueous phase volume (minimum 8.00 mL, typically 15.00 mL for purely aqueous titrations and 9.00 mL for mixed solvent titrations), and pH step between points (ApH=0.10 units recommended). If mixed solvent titrations are carried out on a compound, then additional information needs to be entered; assay direction for second and third titrations (see first assay direction), and additional water volume for second and third assays (automatically calculated when using the cosolvent weight percentage tool).
00 c- 21 SA number of samples (maximum 48) are placed in the autosampler and the pertinent information for each titration (weight of compound, molecular weight etc.) downloaded to the GLpK, instrument from the dedicated PC. The "run assays" option on the GLpKa instrument is selected and the titration run proceeds. At the end of the run, the l 5 titration data is uploaded to the PC and analysed using the pKaLOGP software. The first sample to be analysed is the blank titration. Curve fitting procedures are used to fit the 00 measured data to a theoretical curve allowing the derivation of the exact concentration of 0the HCI solution, and also the values of various parameters (four-plus parameters) which characterise the behaviour of the electrode as a function ofpH. These data are then used in the subsequent analysis of the other samples. The rest of the samples are analysed using further curve fitting procedures that extract the pKas of the compound by fitting the observed data to a theoretical curve. For cosolvent titrations the observed pKas from each sample at different percentages of methanol are analysed using the Yasuda-Shedlovsky procedure in the pKaLOGP software which extraplotes the observed pKas to the true pKas in 100% aqueous solution.
Method C: DPAS (Dip Probe Absorption Spectroscopy) Method This method determines pKas by measuring UV spectra of a compound as a function ofpH. This method is most suitable for compounds where the ionising centre is situated close to an aromatic or conjugated system within the molecule such that a change in the extent ofionisation will lead to a change in the UV spectrum. Due to the good sensitivity of UV spectroscopy, this method is suitable for rather insoluble compounds.
This method requires a blank titration to be run in just the same way as the potentiometric method. However, for the samples, two vials are required for each sample.
Into one vial is placed a small amount of a DMSO solution of the compound (typically pl of a 1.5 mM solution) along with some phosphate buffer to give some pH stability during the titration (typically 100 pL of an aqueous solution prepared from 0.2 g potassium dihydrogen orthophosphate and 100 mL 0.1 M KC1 solution). The titrator will then add water (typically 10 mL) to this solution and then carry out a pH titration while collecting UV spectra at each pH. The second vial should contain and equivalent volume of neat DMSO and an equivalent volume of phosphate buffer. The titrator will then add an equivalent volume of water to this solution and take a UV spectrum of it to act as a 00
O
(N 22 0 reference (this is actually done before the pH titration of the corresponding sample
O
solution).
Again the first sample to be analysed is the blank titration which allows determination of the exact HCI concentration and the values of four-plus parameters. The n 5 pKaUV software is then used to extract the pKas of the compound from the 3 dimensional 00 data (absorbance, wavelength, pH) that was collected during the titration. The software 0 uses a complex algorithm (target factor analysis) to extract the UV spectrum of each protonation state of the molecule as well as each pKa of the molecule from the raw 3 dimensional data.
The invention will now be illustrated by the following non-limiting Examples in which, unless stated otherwise: when given, 'H NMR data is quoted and is in the form of delta values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS)ias Ii an internal standard, determined at 300 MHz or 400 MHz using perdeuterio DMSO-D6
(CD
3 SOCDs), methanol-D4 (CDsOD) or CDCI 3 as the solvent unless otherwise stated; (ii) mass spectra (MS) were run with an electron energy of 70 electron volts in the chemical ionisation (CI) mode using a direct exposure probe; where indicated ionisation was effected by electron impact (El) or fast atom bombardment (FAB) or electrospray (ESI); where values for m/z are given, generally only ions which indicate the parent mass are reported, and unless otherwise stated the mass ion quoted is the positive mass ion (iii) the title and subtitle compounds of the examples and methods were named using the ACD/Index name program version 4.55 from Advanced Chemistry Development, Inc; (iv) unless stated otherwise, reverse phase HPLC was conducted using a Symmetry, NovaPak or Xterra reverse phase silica column; and the following abbreviations are used: DMF N,N-Dimethylformamide HPLC High pressure liquid chromatography RPHPLC Reverse phase high pressure liquid chromatography HATU O-(7-Benzotriazol-l -yl)-N,N,N',N-tetramethyluronium hexafluorophosphate THF Tetrahydrofuran DCM Dichloromethane 00 zi 0 d Day(s) h Hour(s) Smin Minute(s) Preparation 1 S(2R)-l-Amino-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]propan-2-ol 00
CO
OH
Cl /NNHg,' 00 Ste 1: 4-(3,4-Dichlorophenoxy)piperidine 4-Hydroxypiperidine (50 g) was added portionwise to a stirred suspension of potassium tert-butoxide (110.9 g) in THF (900 mL) at room temperature and under nitrogen. The mixture was heated at reflux and 1,2-dichloro-4-fluorobenzene (98 g) added dropwise over 30 min. The mixture was stirred at reflux for another 1 h then cooled downto room temperature, diluted with ethyl acetate (500 mL) and washed with water (500 mL).
The organic phase was diluted further with ethyl acetate (500 mL) and extracted with 1M hydrochloric acid (200 mL). The aqueous extract was adjusted to over pH 10 by addition of a solution of sodium hydroxide and extracted twice with tert-butylmethyl ether (750 mL). The organic extracts were dried over magnesium sulfate, filtered and concentrated under vacuum to yield the sub-title compound as a dark oil which was used as such in the next step.
MS (ESI+ve) 246/248 [M+H-I] H NMR 5 (CDC1 3 1.60-1.70 (2H, 1.97-2.03 (2H, 2.75 (2H, td), 3.15 (2H, dt), 4.29-4.37 (1H, 6.78 (1H, dd), 7.00 (1H, 7.31 (1H, d).
Ste 2: -Azido-3-[ 4 -(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol (2R)-Oxiran-2-ylmethyl 3-nitrobenzenesulfonate (21.1 g) in DMF (300 mL) was treated with triethylamine (22.6 mL) followed by 4 3 4 -dichlorophenoxy)-piperidine The mixture was stirred overnight at 60 0 C. Sodium azide (16 g) was added to the mixture and the reaction was stirred for a further 72 h. The solution was carefully concentrated under vacuum and the residue was diluted with water (600 mL), extracted with ethyl acetate (1500 mL). The organic layer was washed twice with water (500 mL), then brine (200 mL) and concentrated under vacuum to afford an oil.
00
O
c- 24
O
C.)
Step 3: (2R)-1-Amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2 ol The oil from Step 2 was dissolved in wet tetrahydrofuran (225 mL) and was treated N with triphenylphosphine (53.3 The reaction was heated at 60 oC and stirred for 4 h. The n 5 solvent was removed under vacuum, the residue redissolved into 2N hydrochloric acid 00 oo (IL) and the aqueous layer was extracted with ethyl acetate (3 x 700 mL). The aqueous 00 phase was basified with aqueous 2N sodium hydroxide solution and extracted with DCM (3 x IL). The combined organic layers were washed with brine, dried over sodium sulfate, c- filtered and concentrated under vacuum. The crude material was purified by chromatography 7N ammonia in methanol/DCM) to give the title compound as a yellow oil (17 g).
MS (APCI+ve) 319/321 'H NMR 8 (CDC1 3 1.90-1.72 (2H, 2.06-1.91,(2H, 2.46-2.21 (3H, 2.60- 2.49 (1H, 2.65 (1H, 2.72-2.61 (11, 2.82 (1H, 2.94-2.84 (1H1, 3.74-3.62 (1H, 4.0 (1H, app. sept), 6.75 (1H, dd), 7.00 (1H, 7.31 (1H, d).
Preparation 2 (2R)-l-Amino-3-[4-(2,4-dichloro-3-methylphenoxy)piperidin-1-yl]propan-2-ol ca N H Prepared as described in Preparation I using 4-(2,4-dichloro-3-methylphenoxy)piperidine.
MS (APCI+ve) 333/335 [M+H]j 'H NMR 8 (CD 3 0D) 1.92-1.75 (2H, 2.08-1.90 (2H, 2.72-2.57 (1H, m), 2.93-2.72 (4H, 3.35-3.24 (2H, 3.88-3.71 (1H, 4.54-4.37 (1H, 6.94 (2H, d), 7.25 (2H, d).
Preparation 3 -[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-3-methylamino-propan-2-ol
)H
00 A solution of 4-(3,4-dichlorophenoxy)-1-[( 2 R)-oxiran-2-ylmetbyl]piperidine prepared as described in Preparation 1, Step 2 and concentrated from DMF, and O methylamine (2.56 mL 40% v/v aqueous) in ethanol (15 mL) was heated at 60 OC in a sealed vessel for 16 h. The solvent was evaporated at reduced pressure and the residue was purified by flash column chromatography eluting with 8% 7M methanolic ammonia in DCM to give the title compound (0.875 g).
00 00 MS (APCI+ve) 333/335 [M+H] 'H NMR 8 (CDC 3 2.38-2.27 (3H, 2.46 (3H, 2.48-2.42 (2H, 2.54 (1H, 00 dd), 2.56-2.51 (2H, 2.65 (1H, dd), 2.71-2.65 (2H, 2.91-2.86 (1H, 3.86-3.80 c 10 in), 4.32-4.26 (1H, 6.75 (1H, dd), 6.99 (1H, 7.31 (1H, d).
Preparation 4 (R)-1-[4-(2,4-Dichloro-3-methylphenoxy)pieridin-1-yl]-3-(metylamino)prpan- 2-ol 9H I I131' cl N
NH
Prepared as described in Preparation 2 and 3 from 4-(2,4-dichloro-3methylphenoxy)piperidine to give the title compound.
'H NMR 8 (CDCI 3 1.58 2.00 (4H, in), 2.28 2.71 (10H11, 2.46 (3H, 2.87 2.95 (1H, min), 3.49 (1H, 3.82 3.88 (1H, 4.33 4.39 (1H, min), 6.75 (11, 7.19 (1H, d).
Example 1 N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yIJ-2-hydroxypropyl) -6-oxo-2- (trifluoromethyl)-1,6-dihydropyridine-3-carboxamide C I 0O
H!
0 6-Oxo-2-(trifluoromethyl)-1,6-dihydropyridine-3-carboxylic acid (Organic Process Research and Development 1997, 1, 370 378; 0.50g) was dissolved in thionyl chloride mL) and heated at reflux for 3 h. The solvent was evaporated and the residue was azeotroped with toluene (10 mL). The resultant pale yellow solid was dissolved in ethyl 00 C- 26 O acetate (10 mL) and added dropwise to a solution of (2R)-1l-amino-3-[4-(3,4dichlorophenoxy)piperidin-1-yl]propan-2-ol (0.770 g) and triethylamine (1.68 mL) in DCM (25 mL). The mixture was stirred at room temperature for 18 h and the solvents D were evaporated. The residue was dissolved in methanol (20 mL) and heated at reflux for 00' 5 18 h. The solvents were evaporated and purification by RPHIPLC (Novapak, 0.1% ammonium acetate I acetonitrile) afforded the title compound as a colourless solid (0.520 00 g).
The title compound has pKa 5.9 (measured using method and pKa 6.3 (calculatedby ACD).
MS (APCI+ve) 508/510 [M+H]W 'H NMR 6 (CD 3 0D) 1.89 1.78 (2H, 2.10 1.99 (2H, 2.65 2.51 (411, m), 2.99- 2.87 (21, 3.40 3.34 (1H, 3.48 (1H, dd), 4.04- 3.96 (1H, 4.50 4A2 (1H, 6.84 (1H, 6.92 (1H, ddd), 7.14 (11H, dd), 7.41 (11, dd), 7.75 (1H d).
Example 2 N-{(2R)-3-[4-(2,4-Dichloro-3-methylphenoxy)piperidin-1-yl]-2-hydroxypropyl}-6oxo-2-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide a oO OHo
OH
F F 6-Oxo-2-(trifluoromethyl)-1,6-dihydropyridine-3-carboxylic acid (0.100 g) was dissolved in thionyl chloride (2 mL) and heated at reflux for 3 h. The solvent was evaporated and the residue was azeotroped with toluene (5 mL). The resultant pale yellow solid was dissolved in tetrahydrofuran (2 mL) and added dropwise to a solution of(2R)-lamino-3-[4-(2,4-dichloro-3-methylphenoxy)piperidin-1-yl]propan-2-ol (0.161 g, and triethylamine (0.337 mnL) in DCM (5 mL). The mixture was stirred at room temperature for 18h and the solvents were evaporated. The residue was dissolved in methanol (10 mL) and heated at reflux for 3 h. The solvents were evaporated and purification by RPHPLC (Symmetry, 0.1% ammonium acetate acetonitrile) afforded the title compound as a colourless solid (0.520 g).
The title compound has pKa 6.3 (calculated using ACD).
MS (APCI+ve) 522/524 27 00 0 H NMR 5 (CD 3 OD) 1.97 -2.23 (4H, 2.48 (3H, 2.81 3.07 (4H, in), 3.12 3.24 (2H, 3.31 3.52 4.08 -4.18 (1W, in), 4.62 4.69 (1W, 6.89 (1W, d), 7.02 (1W, 7.31 (1W, 7.80 (1H, d).
Examnple 3 ND 5-Bromo-N- {(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl -6- 00 oxo-2-(trifluoromethyl)-1 ,6-dihydropyridine-3-carboxanide 00 Step 1: Ethyl 5-bromo-6-oxo-2-(trifluoromethyl)-1,6-dihydropyridine-3-carboxylate To a solution of ethyl 6-oxo-2-(trifluoromethyl)-1 ,6-dihydropyridine-3-carboxylate (Organic Process Research and Development 1997, 1, 370 378; 0.10 g) in carbon tetrachloride was added N-bromosuccinimide (0.083 The mixture was heated at 80 0
C
for 24 h. Evaporation and the purification by flash column chromatography gave the subtitle compound as a colourless solid (0.10 g).
MS (ES -ve) 311/313 [M-Hf 'H NMR 8 (CDC1 3 1.38 (3W, 4.39 8.34 (1W, s) Ste 2: 5-Bromo-6-oxo-2-(trifluoromethyl)-l ,6-dihydropyridine-3-carboxylic acid Ethyl 5-bromo-6-oxo-2-(trifluoromethyl)-1,6-dihydropyridine-3-carboxylate (0.25 g) was suspended in 30% aqueous hydrochloric acid and heated at reflux for 4 days.
Cooling and filtration gave the subtitle compound (0.210 g).
'H NMR 8 (DMSO-d 6 8.40 (11, 13.40 (1H, 13.70 s).
Step 3: 5-Broio-N- 2
R)-
3 -(4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl} -6oxo-2-(trifluoromethyl)-1 ,6-dihydropyridine-3-carboxamide Made by the method of Example 1 using 5-bromo-6-oxo-2-(trifluoroinethyl)1,6dihydropyridine-3-carboxylic acid (0.10 thionyl chloride (2 mL), (2R)-l-arnino-3-[4- (3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol (0.112 g) and triethylamine (0.244 mL) to yield the title compound as a colourless solid (0.096 g).
The title compound has pKa 4.5 (calculated using ACD).
MS (APCI-ve) 586 [M-H]j 00 C 28 o 'HNMR 8 (CD30D) 1.99 2.13 (21H1, 2.14 2.28 (211, mn), 2.97 3.28 (4H, m), 3.30 3.50 (4H, 4.13 4.22 (1H, mn), 4.63 4.70 (IH, mn), 6.98 (1H, dd), 7.22 (1H, d), 7.44 (1I, 7.88 (1H1, s).
Example 4 N- {(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl}-2,3- 00 dihydro-2-oxo-4-(trifluoromethtiazolecarboxamide 0 CI)yOOJr
NH
Step I 2,3-Diydro-2-oxo4-(trifluoromethyl)-5-thiazolecarboxylic acid To a solution of ethyl 2,3-dihydro-2-oxo4-(trifluoromethyl)-5-thiazolecarboxylic acid (Bionet Research, 2.0 g) in THF (20 mL) was added a solution of lithium hydroxide (0.696 g) in water (20 mL). The mixture was stirred at 500 C for 72 h, cooled to room temperature and filtered. The filtrate was washed with ethyl acetate (10 mL), acidified to pH 3 using dilute hydrochloric acid and extracted with ethyl acetate (2 x 25 mL). The combined organic extractions were washed with water (2 x 50 mL), saturated brine solution, dried (Na2SO4), filtered and concentrated in vacuo to give the subtitle compound as a colourless solid (1.583 g).
MS (APCI-ve) 212 [M-H] "C NMR 8 (CDCl 3 1713 161.1 129.8 39.8 Hz), 122.3 272.4 Hz), 115.1 3.0 Hz).
Step 2: N- {(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-2,3dihydro-2-oxo-4-(trifluoromethyl)-5-thiazolecarboxamide Prepared as in Example 1 using 2,3-dihydro-2-oxo-4-(trifluoromethyl)-5thiazolecarboxylic acid to afford the title compound as a cream foam (0.183 g).
The title compound has a pKa 4.7 (measured using Method B).
MS (APCI-ve) 512/514 1 H NMR 8 (CD30D) 2.06 1.94 (2H, mn), 2.22 2.08 (2H, 3.00 2.86 (2H, ddd), 3.14 3.00 (2H, 3.30 3.18 (21H1, 3.42 3.32 (2H, ddd), 4.11 4.03 (1H, m), 4.64 4.56 (1H, 6.94 (lH, dd), 7.18 (1H, 7.41 (1H, d).
00 c-I 29 o Exmple N- {(26)-3[4-(3-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl} -N-inethyl-2oxo-4-(trifluoromethyl)-2,3-dihydro-1 IND QH 00 5Prepared as Example 1 using (2R)-l-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-3- (methylamino)propan-2-ol (150mg,* 0.45 mmol) and 2-oxo-4-Qirifluoromethyl)-2,3diliydro-1,3-thiazole-5-carboxylic acid (0.096 g) to yield the title compound as a colourless solid (0.085 g).
The title compound has pKa. 6.27 (calculated using ACD).
MS (APCI+ve) 528/530 'HNUR 8 (DMSO0-d 6 90 0 C) 1.79 -1.62 (2k1, m),..203 1.88 (2H, in), 2.62 2.45 (2H, in), 2.93 2.82 (4H, in), 3.00 (3H1, 3.24 (1H1, dd), 3.52 (111, dd), 3.91 (IH, quintet), 4.45 (1H, septet), 6.96 (1H, dd), 7.20 (1H1, 7.46 (1H, d).
Example 6 N- {(2.)-3-[4-(2,4-Dichloro-3-methylphenoxy)piperidin-l-yl]-2-hydroxypropyl} -Ninethyl-2-oxo-4-(trifluoroinethyl)-2,3-dilhydro-l CY O' QH s- 0 F F Prepared as Example 1 using (2R)-1-[4-(2,4-dichloro-3-neietylphenoxy)piperidin- 1 -yl]-3-(methylainino)propan-2-ol 156 g) and 2-oxo-4-(trifluoromethyl)-2,3-dihydroacid (0.096 g) to yield the title compound as a colourless solid (0.09 1 g).
The title compound has pKa 6.3 (calculated using ACD).
MS (APCI-Ive) 54.2/544 'H NMR 5 (DMSO-d 6 90 0 C) 1. 83 1.67 (2H, in), 2.01 1.87 (2H1, in), 2.41 (3H, 2.61 2.50 (2H1, in), 2.93 2.78 (411, mn), 2.99 (3H, 3.24 (111, dd), 3.52 (111, dd), 3.91 (I1H, quintet), 4.47 (11H, septet), 7.05 (1lH, 7.31 (1 H, d).
00 Ci O Example 7 0 N- {(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin- 1 -yl]-2-hydroxypropyl} -2-oxo-4- (pentafluoroethyl)-2,3-dibyro-1,3-thiazole-5-carboxamide i] y4~L NH 000
F
Fi F 00 5 St;R 1: 2-Oxo-4-(pentafluoroethyD)-2,3-dihydro-1,3-thiazole-5-carboxylic acid Ethyl 2-oxo-4-(pentafluoroethyl)-2,3-dihydro-1,3-thiazole-5-varboxylate (J.Het. Chem. 22 1985 1621-1630; 0.240 g) in THF (6 niL) was treated with lithium hydroxide (0.120 g) in water (5 mL) and the mixture was heated at 50 'C for 4 d. The mixture was filtered and the residue was washed with water. The filtrate was washed with ethyl acetate. The aqueous layer was acidified with dilute hydrochloric acid and then extracted with ethyl acetate (3 x 50 mL). The organic extractS were washed with water and brine and then dried over sodium sulphate, filtered and evaporated to yield the subtitle compound as a solid (0.13 g).
Step 2: N- {(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-I -yl]-2-hydroxypropyl} -2-oxo-4- (pentafluoroethyl)-2,3-dihydro-l Prepared as Example 1 using (2R)-1-amino-3-[4-(3,4-dichloropenoxy)piperidin-lyl]propan-2-ol (0.158 g) and 2-oxo-4-(pentafluoroethyl)-2,3-dlydro-l,3-thiazole-5carboxylic acid (0.130 g) to yield the title compound as a colourless solid (0.074 g).
The title compound has pKa 6.1 (calculated using ACD).
MS (APCI+ve) 564/566 'H NMR B(DMSO-d 6 1.86 1.72 (2H, 2.08 1.96 (2H, in), 2.84 2.59 (4H, 3.10- 2.90 (11, mobscured), 3.28 -3.16 (3H, 3.85 (1H, quintet), 4.53 septet), 6.98 (1H, dd), 7.23 (IH, 7.47 7.48 (1H, s).
Example 8 N- {(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin- 1 -yl]-2-hydroxypropyl) 1H-i ,2,3-triazole-4-carboxamide CI PQCNNNH 00 31 Prepared as Example 1 using 5-methyl-IH-1,2,3-triazole-4-carboxylic acid N_ (Berichte 1963 96, 802 812;'0.060 g) to yield the title compound as a colourless solid (0.063 mg).
The title compound has a pKa 7.5 (measured using Method and pKa (calculated using ACD).
IND MS (APCI+ve) 428/430[M+H]+
V)
00 'H NMR 8 (DMSO-d 6 1.73 1.60 (2H, 1.97 1.86 (21, 2.41 2.28 (4H, 2.45 (3H, 2.79 2.67 3.43 3.24 (2H, 3.78 (11, quintet), 4.39 (1H, 00 septet), 6.95 (IH, dd), 7.18 (1H, 7.44 7.90 (lH, t), Example 9 N- 4 -Dichloro-3-methylphenoxy)piperidin-1-yl]-2-hydroxypropyl) methyl-IH-1,2,3-triazole4-carboxamide
NH
Prepared as Example 1 using (2R)-l-amino-3-4-(2,4-dichloro-3iethylphenoxy)piperidin-I-yl]propan-2-ol (0.158 g) and 5-niethyl-1H-1,2,3-triazole-4carboxylic acid to yield the title compound as a colourless solid (0.037 g).
The title compound has a pKa 7.5 (calculated using ACD).
MS (APCI+ve) 442/444 'H NMR 8 (DMSO-d 6 90 OC) 1.78 1.65 (2H, 1.97 1.86 (211, 2.43 2.32 (4H, 2.41 (31, 2.45 (311, 2.79 2.67 (211, 3.28 (11, dt), 3.40 (IH, dt), 3.78 (IH, quintet), 4.43 (1H1, septet), 7.03 (1H1, 7.30 (1H, 7.89 (11, t).
Example 5-Cyano-N- {(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-i -yl]-2-hydroxypropyl) -6oxo-2-(trifluoromethyl)-1 ,6-dihydropyridine-3-carboxamide ci o H cJJ .0 CQH F3 N 0 5-Cyano-6-oxo-2-(trifluoroinethy1)-1 ,6-dihydropyridine-3-carboxylic acid (Farnaco 1997, 52(5), 331 337; 0.115 g) was dissolved in thionyl chloride (3 nL) and heated at reflux for 2 h. The solvent was evaporated and the residue was azeotroped with toluene (10 mL). The resultant solid was dissolved in THF (5 mL) and added dropwise to a solution of (2R).l-[4-(3,4-dichlorophenoxy)-piperidin-1-yl]-3-methylamino-propan-2-oI (0.150 g) and triethylaiine (0.3 rL) in DCM (5 nL). The mixture was stirred at room tn 5 temperature for 18 h and the solvents were evaporated. Purification by RPHPLC 00 (Novapak, 0.1% anmonium acetate acetonitrile) and normal phase chromatography (NH3/methano/DCM) afforded the title compound as a colourless solid (0.123 g).
The title compound has a pKa 3.4 (calculated using ACD).
MS (APCI+ve) 533/535 [M+jII] 'H NMR 8 (CD 3 OD) 2.13 1.99 (2H, 2.28 2.13 (2H, 3.10 (2H1, dt), 3.34- 3.14(2H, 3.50-3.36(4H, 4.21-4.12 (1H, 4.71-4.63 (11, 6.96 (1H1, dd), 7.21 (11, 7.42 (11, 7.85 (11, s).
Example 11 5-Cyano-N- {(2R)-3-[4-(2,4-dichloro-3-methylphenoxy)piperidin- 1-yl]-2hydroxypropyl)-6-oxo-2-(trifluoromethyl)-l ,6-dihydropyridine-3-carboxamide c? H CF 0i Prepared as Example 1 using (2R)-1-amino-3-[4-(2,4-dichloro-3methylphenoxy)piperidin-l-yl]propan-2-ol to yield the title compound as a colourless solid (0.121 g).
The title compound has a pKa 3.0 (easured using Method and pKa 3.4 (calculated using ACD).
MS (APCI+ve) 547/549 [M+HJ' 1H NMR 6 (DMSO-d 6
+ND
4 OD) 1.72 1.61 (211, 1.93 1.84 (21, 2.37 2.24 (411, 2.40 (3H, 2.72 2.63 (211, 3.07 (1H, dd), 3.23 (lH, 3.71 (IH, quintet), 4.48 (1H, septet), 7.10 (1H, 7.34 (11, 7.66 (11, s).
Example 12 5-Cyano-N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l -yl]-2-hydroxypropyl} -6oxo-2-phenyl-1 ,6-dihydropyridine-3-carboxamide 33 00 I 0~ o cN.
5-Cyano-6-oxo-2-phenyl-1,6-dihydropyridine-3-carboxylic acid (European Jounal INDOfMedicinal Chemisiy 24(5), 517 519, 1989; 0.112 g) was dissolved in thionyl chloride 00 (4 mL) and heated under reflux for 2 h. The solvent was removed in vacuo and the residue was azeotroped with toluene (10 The resultant pale yellow solid was dissolved in 00 THF (4 mL) and added dropwise to a solution of (2R)-1-amino-3-[4-(3,4dicllorophenoxy)piperidin-1-yl]propan-2-ol (0.150 g) and triethylamine (0.7 mL) in DCM (2 nL). The mixture was stirred at room temperature overnight and the volatiles were removed in vacuo. The residue was dissolved in acetonitrile (6 mL) and purification by RPHPLC (Novapak 0.1% ammonium acetate acetonitrile) afforded the title conpojundas a white solid (0.025 g).
The title compound has a pKa 3.0 (measured using Method and pKa 6.3 (calculated using ACD).
MS (APCI+ve) 541/543 'HNMR B(DMSO-d 6 1.54 1.64 (211, 1.84 1.95 (2H, 2.12 2.35 (4H, 2.62- 2.73 (2H, 2.92 3.00 (1H, 3.11 -3.20 (11, 3.53 -3.61 (1 in), 4.38 4.49 (1H, 4.56 4.76 (11, br 6.98 (11, dd), 7.25 (11, 7.42 7.53 (611, 8.11 (11H, 8.23 (11H, s).
Example 13 5-Cyano-N-{(2R)-3-[4-(2,4-dichitoro-3-methylphenoxy)piperidin-l -ylI-2hydroxypropyl} -6-oxo-2-phenyl-1 ,6-dihydropyidine-3-carboxamide IYY 11 ci O)D N NI0 0 5-Cyano-6-oxo-2-penyl-1,6-dihydropyridine-3-carboxylic acid (European Journal ofMedicinal Chetisty 24 517 -519, 1989; 0.112 g) was dissolved in thionyl chloride (4 mL) and heated under reflux for 2 h. The solvent was removed in vacuc and the residue 00 34 was azeotroped with toluene (10 mL). The resultant pale yellow solid was dissolved in THF (4 nL) and added ropwise to a solution of (2R)'1-amino-3-[4-(2,4-dichlro-3methylphenoxy)piperidin-I-yl]propan-2-ol (0.150 g) and triethylamine (0.7 ml) in DCM (2 mL). The mixture was stirred at room temperature overnight and the volatiles Were removed in vacuo. The residue was dissolved in acetonitrile (6 mL) and purification by RPHPLC (Novapak, 0.1% ammonium acetate acetonitrile) afforded the title compound as 00 a dry yellow powder (0.011 g).
c The title compound has a pKa 6.3 (calculated using ACD).
00 MS (APCI+ve) 555/557 '11 NMR S(CDC1 3 1.92 2.01 (211, 2.06 2.21 (3H, 2.47 (3H, 2.50 2.56 (2H, 2.76 2.83 (11, 2.87 (1H, td), 2.96 3.05 (211, 3.06 3.15 W), 3.35 3.43 (11, 4.50 -4.55 (1H, 6.33 6.39 (1H, 6.74 (1H, 7.22 (11, d), 7.47 7.51 (511, in); 7.51 7.57 (1H, 8.22 (lH, s) Exampe 14 N- 4 -(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}3-methyl- 2,6-dioxo-1 ,2,3,6-tetrahydropyrimidine-4-carboxamide Step 1: 3-Methyl-2,6-dioxo-1 ,2,3,6-tetrahydropyrimidine-4-carboxylic acid The subtitle compound was synthesized according to the procedure described in Phariazie 48 1993, H. 11 861 862.
Step 2: N- {(2R)-3-[4-(3,4-Dicblorophenoxy)piperidin- 1 -yl]-2-hydroxypropyl -3-methyl- 2,6-dioxo-1,2,3,6-tetrahydropyrinidine-4-carboxamide 3-Methyl-2,6-dioxo-l,2,3,6-tetrahydropyrimidineA-carboxylic acid (Pharnmazie 48 1993, 11, 861 862; 0.173 g) was dissolved in thionyl chloride (8 mL) and heated under reflux for 2 K The solvent was removed in vacuo and the residue was azeotroped with toluene (10 mL). The resultant pale yellow solid was dissolved in THF (4 iL) and added dropwise to a solution of (2R)-1-amino- 3 4 -(3,4-dichlorophenoxy)piperidin-lyl]propan-2-ol (0.325 g) and triethylamine (1.56 mL) in DCM (4.5 nL). The mixture was stirred at room temperature overnight and the volatiles were removed in vacuo. The 00 residue was dissolved in acetonitrile (6 mL) and purification by RPHPLC (Novapak, 0. 1% ammonium acetate acetonitrile) followed by trituration with DCM afforded the title 0 compound as a yellow powder (0.008 g).
The title compound has a pKa 6.9 (calculated using ACD).
MS (APCI+ve) 471/473
IND
'H NMR 8 (CD 3 OD) 1.26 1.36 (2H, 1.78 1.85 (2H, 1.99 2.05 (2H, i), 00 2.55 2.60 (21, 2.83 -2.95 (2H, 3.11 3.14 (1H, 3.32 (3H, 3.49 3.52 (11, 3.89 4.01 (11, 4.41 4.47 (11, 5.58 (IH, 5.78 (1H, 6.88 6.91 (1H, m),7.11 (1H,d) 7.38 (1H, d).
C-I ExaDe N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin- 1-yl]-2-hydroxypropyl)-2,6-dioxo 3-(2,2,2-trifluoroethyl)-1, 2 ,3,6-tetrahydropyrimidine4-carboxamjde Pharmazie 81993, H. i 861"- 862.
Step 2: N-(2R)-3 4-(3,4-Dichlorophenoxylpiperidi- y]2hdoyrpl 26doo 3-(2,2,2-lrifluoroethyl)-1 2 3 6 -tetrahydropyrimidine-~-carboxamide To a solution of 2 l-anino- 3 -[4-(3,4-dichlorophenoxy)piperii. 1-y]propan..2.
ol (0.134 g) in dry DMF (3 inL), was added N,N-diisopropylethylamine (0.14 mL), 2,6dioxo-3-(2,2,2-trifluoroethyl) 1 2 3 6 -tetahydropyriinidine-4-carboxylic acid (0.100 g) and HAT e (0.178 The reaction mixture was stirred at 0 C under an atrospere of nitrogen for 20 me, then quenchdith saturated sodium bicarbonate solution (10 mL), and allowed to stand overight. The mixture was extracted with ethyl acetate (3 x 10 m-L).
The combined organics were washed with brine (2 x 10 mL), dried over anhydrous magnesium sulfate, and the volatiles were removed in vacuc to give an oil (0.205 g).
Purification by RPHPLC (Novapak, 0.1% ammonium acetate acetonitrile) afforded the title compound (0.028 g) as a dry yellow powder.
00 C-I .36 The title compound has a pia 5.9 (calculated using ACD).
MS (APCIve) 539/541(M+H) 1 HNMR (CD 3 OD) 5 1.83 1.68 (2Hi 2.03 1.90(21L 2.29- 2.24(1H m), 2.45 2.34 (1H, rn), 2.69 2.51 (4H, 2.97 2.84 (2H, 3.03 (11, quintet), 3.26 3.23 (1H, 3.34 3.32 (1H, 3.37 3.35 (1H, 3.90 (1H, quintet), 4.40 (1H, quintet), 5.39 (1H, 5.93 (1H, 6.82 (1H, dd), 7.04 (11, d) 7.30 (11, d).
00 Example 16 5-Cyano-2-cyclopropyl-N-[(2R)-3-[4-(3,4-dichlorophenoxy)- -piperidinyl]-2 hydroxypropyl)-l ,6-dihydro-6-oxo-3-pyridinecarboxanide a) 7oNK"oH
N
A stirred solution of 5-cyano-2-cyclopropyl-6-oxo-1,6-dihydropyridine-3carboxylic acid (0.080 g) Med. Chem. 2002, 45, 1887) in thionyl chloride (2.5 nL) was heated at reflux for 2 h. Thionyl chloride was removed from the cooled solution in vacuo.
The residue was dissolved in TIP (4 mL) and this solution was added dropwise.at room temperature to a solution of (2R)-1-anino-3-E4-(3,-dichlorophenoxy)pipeidinyl]propan-2-ol (0.125 g) and triethylaninne (0.7 mL) in DOM (2 iL) before stirring overnight. The reaction mixture was concentrated in vacuo and redissolved in 9 1 acetonitrile/water (4 nL) before subjecting to RPHPLC (gradient 0.1% ammonium acetate/acetonitrile 95% to 50%) to yield a white solid (0.022 g).
The title compound has a pia 3.8 (measured using Method and pKa (calculated using ACD).
MS (ES+ve) 505/507 [M+HJ+ 'H NMR 8 (DMSO-d 6 1.02 1.08 (2H, 1.11 1.17 (211, 1.57 1.68 (2H, 1.89- 1.97 (211, 2.30-2.43 (414, 2.53 -2.61 (111, 2.72- 2.85 (211, 3.05 3.14 (1H, 3.74 3.81 (11, 4.42- 4.49 (11, in), 6.98 dd), 7.26 7.50 (1H, 8.10 (lH, 8.32 (1H, resonance at -3.3 (1H, m) obscured by EDO.
Examrple 17 5-Cyano-2-cyclopropyl-N- [4-(2,4-dichloro-3-methylphenoxy)- lpiperidinyll-2-hydroxypropyllJ- 1,6-dihydro-6-oxo-3-pyridnecarboxamide 00 37
OO
C 0 The title compound has pKa 7.5 (calculated using ACD).
00 MS (ES+ve) 519/521 'H NMR 8 (DMSO-d 6 1.00 1.07 (211, 1.10 1.17 (2H, 1.62 1.73 (2H, 00 5 1.86 1.93 (21-1, 2.30 2.39 (4H, 2.40 (3H, 2.52- 2.61 (1H, 2.66 2.78 (ZH, 3.04 3.13 (11, 3.73 3.80 (111, 4.46 4.54 (1H, 7.10 (11, 7.35 (1H, 8.07 (1H, 8.29 (1H, resonance at -3.3 (1H, m) obscured by HDO.
Example 18 N- ,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl} [(methysulfonyl)amino]-4-(trifluoromethyl)nicotinamide 0 *0 0 F F F Step 1: 6-Chloro-N-{(2R)-3-[4-(3,4-dichloropbenoxy)piperidin- 1-yl]-2-hydroxypropyl}-4- (trifluoromethyl)nicotinamide A solution of 4-trifluoromethyl-6-chloronicotinoy chloride (0.585 g) in TBFF (3 mL) was added dropwise at room temperature to a stirred solution of (2R)-1-amnino-3-[4- (3,4-dichlorophenoxy)piperidin- 1-yl]propan-2-oI (0.73 5 g) and triethylamine (0.7 mL) in DCM (2 mL). After 18 b, the reaction mixture was concentrated in vacuo and subjected to flash column chromatography (eluent 96: 4 dichloromethane/7 N ammonia in methanol) to yield a yellow oil (1.02 A small amount (0.1 g) was redissolved in 9: 1 acetonitrile/water (4 mL) and subjected to RPHPLC (gradient 0.1% ammonium acetate/acetonitrile 95% to to yield a white solid (0.025 g).
MS (ES+ve) 526/528 1H NMR 5 (CD 3 0D) 1.66 1.80 (211, mn), 1.87 2.00 (211, 2.42 2.57 (4H, i), 2.76 2.90 (211, 3.27 (11, dd), 3.44 (11, dd), 3.86 3.95 (11, 4.30 4.41 (IH, i), 6.80 (11, dd), 7.02 (II, 7.29 (11, 7.78 (IH, 8.56 (lH, s).
Step 2: N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-6- [(methylsulfonyl)amino]-4-(trifluoromethyl)nicotinamide 00
O
c-I 38 A stirred solution of 6-chloro-N- {(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-y]- 2-hydroxypropyl}-4-(trifluoromethyl)nicotinamide (0.28 methanesulfonarnide (0.12 g) and potassium carbonate (0.148 g) in N-methyl-2-pyrrolidinone was heated under microwave irradiation (100 W) at 100 0 C for 15 min. The reaction mixture was 0 5 concentrated in vacuo and redissolved in 4 1 1 acetonitrile/ water/acetic acid (6 mL) and subjected to RPHPLC (gradient 0.1% ammonium acetate/acetonitrile 95% to to yield 00 a white solid (0.025 g).
The title compound has a pKa 5.3 (measured using Method B).
MS (ES+ve) 585/587 IH NMR 8(CD 3 0D) 1.86 2.02 (2H, mn), 2.06 2.20 (2H, 2.74 2.98 (41, m), 3.07 3.22 (2H, 3.24 (311, 3.36 3.56 (2H11, 4.05 -4.16(1H, mn), 4.52 4.62 (1H, 6.95 (1H, dd), 7.12 (11, 7.18 (1H, 7.42 (1H, 8.44 (1H, a) JExample 19 N- {(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-5-[(2,22trifluoroethyl)thio]-1l-1,2,3-triazole-4-carboxamide 0 SJCF F Step 1: Ethyl 1-(4-methoxybenzyl)-5-[(2,2,2-trifluoroethyl)thio]-1H-1 ,2,3-triazole4carboxylate Sodium hydride (0.0 18 g) was added to a solution of 3,3,3-trifluoroethanol (0.060 mL) in dry DMF (1.5 mL). After stirring at room temperature for 30 min a solution of ethyl 5-chloro-1H-1,2,3-triazole-4-carboxylate (0.20 g, J.Chem. Soc. Perlkin I, 1982, 627) in dry DMF (1 mL) was added. The mixture was heated at 80 oC for 18 h then cooled and partitioned between diethyl ether (50 mL) and water (50 mL). The aqueous layer was re-extracted with diethyl ether (2 x 50 mL) and the combined extracts were dried over anhydrous sodium sulfate. Concentration in vacuo and chromatography on silica (0-50% gradient EtOAc isohexane) gave the subtitle compound (0.127 g).
MS (ES+ve) 376 [M+H] '1H NMR 8(CDCl 3 1.44 (3H, 3.66 (2H, 3.78 (31H1, 4.46 (2H, 5.62 (2H, 6.89-6.83 (2H, 7.29-7.24 (2H, m).
00 39 Step 2: Ethyl 5-[(2,2,2-trifluoroethyl)thio]-IH-1,2,3-triazole-4-carboxylate ~Ethyll 1-(4-methoxybenzyl)-5-[(2,2,2-trifluoroethyl)thio]-H-1,2,3-triazole-4- O carboxylate (0.127 g) was dissolved in trifluoroacetic acid (2 mL) and heated at 65 C for 4 h. The trifluoroacetic acid was evaporated in vacuo and the residue was azeotroped with toluene (3 x 10 mL) then dried under vacuum to afford the subtitle compound (0.086 g).
INDMS (ES-ve) 234 [M-HF] tn 00 'H NMR 8(CDCI 3 1.44 (3H, 3.89 (2H, 4.46 (2H, q).
Ste 3: 5-[(2,2,2-Trifluoroethyl)thio]-1H-1,2,3-triazole-4-carboxylic acid Ethyl 5-[(2,2,2-trifluoroethyl)tbio]-1H-1,2,3-triazole-4-carboxylate (0.086 g) was suspended in 1N aqueous sodium hydroxide solution and heated at 70 oC for 3 h. The reaction mixture was filtered and then acidified with concentrated hydrochloric acid.
Concentration in vacuo afforded a colourless solid which was washed with ice cold water to afford the subtitle compound (0.080g) MS (ES-ve) 226 [M-H] '11 NMR S(DMSO-d 6 4.09-4.22 (2H, 13.51 (11, 15.75 (1H1, s).
Step 4: N-((2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl}-5-[(2,2,2trifluoroethyl)thio]-1H-1,2,3-triazole-4-carboxamide 5-[(2,2,2-Trifluoroethyl)thio]-1H-1,2,3-triazole-4-carboxylic acid (0.080 g) was dissolved in DCM (2 mIL) and treated with oxalyl chloride (0.060 mL) and DMF (1 drop).
The solution was stirred at room temperature for 1 h then concentrated in vacuo and azeotroped with anhydrous toluene (5 mnL). The residue was redissolved in dry 'ITF and added dropwise to a stirred solution of( 2 R)--amino-3-[4-(3,4-dichlorophenoxy)piperidin- 1-yl]propan-2-ol (0.108 g) and triethylamine (0.142 mL) in DCM. The mixture was stirred for 1 h, the solvent was evaporated in vacuo and the product purified by RPHPLC (gradient 0.1% ammonium acetate/acetonitrile 50% to 5%).to afford the title compound as a colourless solid (0.058 g).
The title compound has a pKa 5.2 (measured using Method and pKa 4.6 (calculated using ACD).
MS (ES+ve) 528/530 'H NMR 8(CD 3 OD) 1.92 1.84 (2H1, in), 2.09 1.98 (2H, in), 2.92 2.72 (4H, m), 3.13 3.04 (211, in), 3.42- 3.32 (2U, m) ,3.82 (211, 4.03 3.97 (11, 4.50 4.43 (1H, 6.83 (11, dd), 7.07 (11, 7.30 (1H1, d).
tn 00 5 Example 4-[({(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} amino)- 000 00 carbonyl]-l-naphtiioic acid OH OH To a solution of naphthalene-1,4-dicarboxylic acid (0.100 (2R)-1-amino-3-[4- (3,4-dichlorophoxy)piperidin-1-yl]propan-2-ol (0.147 g) and triethylamnine (0.193 nL) in N-methyl-2-pyrolidinone (20 mL) was added PyBrOP (0.258 The reaction mixture was stirred for 16 h and the solvent was removed in vacuo. The residue was purified by RPHPLC (Symmetry, 0.1% ammonium acetate acetonitrile) to afford the title compound as a colourless solid (0.050 g, The title compound has pia 3.1 (calculated using ACD).
MS (APCI+ve) 517/519 [M+HJ+ 'IHNMR 8(CD 3 OD) 2.02 2.30(411, 3.09 3.20 (2H, in), 3.22 3.30 (211, m), 3.38 3.47 (2H, 3.51 3.67 (2H, in), 4.26- 4.35 (11, 4.66- 4.73 (11, in), 6.99 (11, dd), 7.23 (11, 7.45 (11, 7.53 7.59 (211, in), 7.64 (1H, 7.69 (11, 8.23 8.26 (11, in), 8.57 8.60 (11, m).
Exmple 21 N- {(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} -2- [(methylsulfonyl)aiino]-4-(trifluoromethyl)-1,3-thiazole-5-carboxanide CIH
SO
2 Me 0 CF 3 Step 1: 2-[(Methylsulfonyl)a-n.ino]-4-(trifluoromethyl)-1,3-thiazole-5-carboxylic acid To a stirred solution of ethyl-2-amino-4-(trifluoromethyl)-5-thiazole crboxylate (1.2 g) and triethylamine (2.1 mL) in THF (12 niL) was added methane sulfonic anhydride 00 41 (1.74 g) in small portions at room temperature. After 2 h, the reaction mixture was o concentrated in vacuo and the residue was stirred in dioxane (5 mL) and aqueous 1 N NaOHl (5 niL) for 16 h. The reaction mixture was cdncenliated in vacuo and to the residue in water (20 niL) and THF (30 mL) was added lithium hydroxide monohydrate (1.8 g) before being heated at 50 0 C for 12 hi. To the cooled reaction mixture was added 1 N 00 aqueous hydrochloric acid (30 xnL) and extracted into EtOAc (2 x 25 mL), dried over sodium sulfate, filtered, and concentrated in vacuo.
00 'H NMR B(DMSO-do) 3.26 (3H1, n).
Step 2: N- {(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl)-2-' [(methylsulfonyI)amino]-4-Qtrifltuoromethyl)-1,3-thiazole,-5-caboxamide A stirred solution of 2-[(methylsufonyl)amino]-4-(rfluoromethyl)-l,3-thiazole-5carboxylic acid (0.145 g) in thionyl chloride*(3 niL) was heated at reflux for 2 h. Thionyl..
chloride was removed from the cooled solution in vacuo. The residue was dissolved in TIE (4 niL) and this solution was added dropwise at room temperature to a solution of (2R)-1-amino-3-[4-(3,4-dchlorophenoxy)piperidin-1-yl]propan-2-ol (0.144 g) and triethylainine (0.7 inL) in DCM (2 rnL) before stirring overnight.
The reaction mixture was concentrated in vacuo and redissolved in 9: 1 acetonitrile/water (4 mL) before being subjected to RPIIPLC (Novapak, gradient 0.1% amimonium acetate/acetonitrile 95% to to yield a white solid (0.028 g).
Retention time: 1 .46 min (reverse phase analytical HPLC (Hewlett Packard Series 1 100): Waters "Symmetry" C8 column 3.5pm; 4.6 x 50mm column gradient 0. 1% amnmonium acetate/acetonitrile 75% to 5% in 3 mini; flow 2rnnn).
The title compound has a pKa 7.5 (measured -using Method B).
MS (ES+ve) 59 1/593 'H NMR 5(CD 3 OD) 1.88 2.04 (211, mn), 2.05 2.19 (2H1, in), 2.82 (311, 2.97 (111, 3.10 (lH, 3.14 3.41 (4H1, mn), 4.05 4.14 (lH, in), 4.55 4.62 (111, in), 6.87 (111, dd), 7.12 (111, 7.32 (111, 2 resonances obscured.
Examle 22 N- {(2R)-3-[4-(4-Chloro-2-methylphenoxy)piperidin-1-yl]-2-hydroxypropyl} -2oxo-4-(tifuoroinethyl)-2,3-dihydro-1 00 C-I -42 N ON
NHS-K
CIj
A
0
CF
3 00 Prepared as Example 4 from (2R)-lamino-3-[4-(4-chloro-2-methylphenoxy)piperidin-1-yl~propan-2-ol [W02003068743(AI)J to give a white solid (0.046 g).
0 0 Retention time: 1.37 min (reverse phase analytical HPLC (Hewlett Packard Series 0 5 1100): Waters "Symmetry" C8 column 3.5pm; 4.6 x 50mm column gradient 0.1% c-I ammonium acetate/acetonitrile 75% to 5% in 3 min; flow 2mL/min).
The title compound has pKa 6.1 (calculated using ACT).
MS (BS+ve) 494/496 [M+H] 4 'H NMR B(CD30D) 1.97 2.10 2.11 2.21 (2H, 2.22 (3H, 2.93 (1H, dd), 3.02 (1H, dd), 3.08- 321( 2H, 3.21 3.30 (2H, rp, 3.33 3.42 (2H, 4.06 4.13 (1H, 4.57 4.63 (lH, my, 6.92 (1H, 7.11 (iI, dd), 7.15 (IH, d).
Epmmle 23 [5-[(((2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2hydroxypropyl) amino)carbonyl-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl]acetic acid rCOlH H OH NO 0 CF 3 Step 1: 1-(2-Methoxy-2-oxoethyl)-6-oxo-4-(trifluoromethyl)- 1 ,6-dibydropyridine-3carboxylic acid To a stirred suspension of 6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3carboxylic acid (0.207 g) and potassium carbonate (0.553 g) in methanol (5 mL) was added methyl bromoacetate (0.104 nL) at room temperature. After 16 h, the reaction was not complete, so further methyl bromoacetate (0.15 mL) was added. After a further 16 h, the mixture was concentrated in vacuo before the addition of 1 N aqueous hydrochloric acid mL) and extracted into ethyl acetate (3 x 25 raL), dried over Na 2
SO
4 filtered, and concentrated in vacuc to leave a white solid (300 mg).
MS (ES-ye) 278 'H NMR 6(DMSO-d 6 3.70 (3H, 4.88 (2H, 6.91 (IH, 8.68 (114, 13.25 00 43 (1B, br s).
o Step 2: Methyl [5-[({(21?)-3-[4-(3,4-dicblorophenoxy)piperidin 1 -yI-2hydroxypropyl}amino)carbonyl]-2-oxo4-(trifluoromethyl)pyridim-l(2UJ-yl]acetate A stirred solution of l-( 2 -methoxy 2 -oxoethyl)6-oxo4.(trifluoromethyl).1,& dihydropyridine-3-carboxylic acid (0.140 g) in thionyl chloride (4 mL) was heated at 00 reflux for 2 h. Thionyl chloride was removed from the cooled solution in vacuo. The residue was dissolved in TEW (4 mL) and this solution was added dropwise at room temperature to a solution of -amino-3-[ 4 3 4 -dichlorophenoxy)piperidin..
yl]propan-2-ol (0.144 g) and triethylamine (0.7 mL) in DCM (2 mL) before stirring overnight- The reaction mixture was concentrated in vacuo and used directly in the subsequent step.
Ste,3: 2
R)-
3 4 3 4 Dichlorophenoxy)pipe in..y1]2hydroropylamjo) carbonyl]-2-oxo-4-(trifluoromethyl)pyridin 2 H)-yl] acetic acid A solution of methyl 2 R)-3-[4-(3,4-dichlorophenoxy)piperiin1 -yl]-2hydroxypropyl)am o)carbonyl]-2-ox re l ri (0.1 g) and lithium hydroxide (0.022 g) in THE (3 nL) and water (1 mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacua and redissolved in 9 1 acetonitrile/water (4 mL), and acidified to pH 5 with acetic acid before being subjected to reverse phase 1PLC (Novapak, gradient 0.1% ammonium acetate/acetonitrile 95% to to yield a white solid (0.032 g).
Retention time: 1.29 min (reverse phase analytical HPLC (Hewlett Packard Series 1100): Waters "Symmetry" C8 column 3.51im; 4.6 x 50mm column gradient 0.1% ammonium acetatelacetonitrile 75% to 5% in 3 min; flow 2mL/min).
The title compound has pKa 3.6 (calculated using ACD).
MS (ES+ve) 566/568 [M+HJ+ 'H NMR 5(CD 3 OD) 1.97 2.07 (2H, in), 2.08 2.23 (2H, 2.93 dd), 3.03 (11 dd), 3.06 3.16 (2H, 3.21 3.29 (2H, 3.36 (IH, dd), 3.45 (11, dd), 4.08 4.15 (1 H, 4.58 (2H, 4.59- 4.65 (11, 6.85 (IH, 6.95 (lH, dd), 7.19 (lH, 7.41 (1H, 8.07 (111, s).
Example 24 00 44 cI N-{(2R)3-[4-(3,4-Dichloro-2-methylpefoxy)Piperidl-1 -yl]-2-hydroxypropyl-2oxo-4-(trifluorometby1)-2,3-dihydro-1 NO N 00 0- F F The title compound was prepared as Example 4 and was obtained as a white solid 00 (0.10 g).
The title compound has pKa 6.1 (calculated using ACD).
MS (APCI4ve) 528/530 EM+H1+ 'H NMR B(CD3QD) 1.87 2.02 (2H, 2.02 2.21 2.25 (3H, 2.79 2.97 (2H, 2.97 3.20 (2H, in), 3.22 3.33 (4H, 4.00 (lE, td), 4.54 (1H, 6.87 to (iH, 721 (1H, dd).
Example N- {(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-y]-2-hydroxypropyl fluorophenyl)-2-oxo-2,3-ihdro-1,3-thiazole-5-carboxamide
QH
14N NH 0/
F
Step 1: Methyl 4-(4-fluorophenyl)-2-oxo-2,3-dihydro- Prepared according to J.Het.Cheni. 22,1985, 1621-30 using methyl (2)-3-amino- 3.(4-fluorophonyl)amylate [Angew. Chem. 2003, 42(8), 913-6]. Obtained as a yellow solid (3.67 g).
Retention time: 2.62 min (reverse phase analytical HPLC (Hewlett Packard Series 1100): Waters "Symmetry" C8 column 3.5pni; 4.6 x 50mm column gradient 0.1% ammonium acetate/acetonitrile 95% to 50% in 3 min; flow 2xnmin).
MS (ES-ye) 252 [M-If- Step 2: 4-(4-Fluorophenyl)-2-oxo-2,3-lihydro-1,3-thiazole-5-carboxylic acid Prepared as for Example 4. Obtained as pale yellow solid (0.38 g).
MS (ES +ve) 240 00 c-I o 'HI NMR 6(DMSO-d6) 7.24 7.33 (2H, in), 7.57 7.64 (2H, in), 12. 10 (1 H, s).
Step 3: N- 1(2R)-3 -[4-(3,4-Dichlorophenoxy)piperidin- 1 -yl]-2-hydroxypropyl) INDfluorophenyl)-2-oxo-2,3-dihydro- 1,3-thiazole-5-carboxamide 00 5 Prepared as Example 4. Obtained as white solid (0.06 g).
c-I The title compound has a pKa 7.4 (measured using Method B).
00 MS (APCI+ve) 538/540 1 Hj NMR 8(D.MSO-d 6 1.51 1.63 (2H, mn), 1.83 1.93 (2H, in), 2.15 2.29 (4H, mn), 2.59 2.71 (2H, in), 2.97 3.04 (1HjI-m), 3.15 3.21 (1H, mn), 3.60 (1H, quintet), 4.42 (1H, septet), 4.60 (1H, 6.98 (1H, dd), 7.25 (1H, 7.26 7.34 (3H1, in), 7.49 (11L, d), 7.56 (2H, q).
Example 26 AT- (2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-5.(4.
fluorophenyl)-lH-1,2,3-triazole-4-carboxamide C~y~~.OQH =N 0 Step 1: Methyl 5-(4-fluorophenyl)- 1H-l,2,3-triazole-4-carboxylate Sodium (0.25 g) was added gradually to dry absolute ethanol (4.6 mL). Methyl 3- (4-fluorophenyl)-3-oxopropanoate (1.44 g) was added followed by 4-methoxybenzyl azide.
The mixture was heated at reflux for 18 h and was then cooled and concentrated in vacuio.
The mixture was poured into ice water and acidified with dilute hydrochloric acid. The resulting precipitate was filtered and dried to yield a yellow solid. This was heated at 65 0
C
in trifluoroacetic acid (8 mL) for 8 b. The mixture was concentrated in vacuo and azeotroped with toluene and then treated with ethyl acetate and filtered to yield the title compound as a yellow solid (0.5 Used without purification.
Step 5-(4-Fluorophenyl)-lH- 1, 2 ,3-triazole-4-carboxylic acid Prepared as for Example 8. Obtained as a white solid.
00 C-I 46 0 Retention time: 0. 87 min (reverse phase analytical IPLC (Hewlett Packard Series 1100): Waters "Symmetry" C8 column 3.5[tn; 4.6 x 50mm column gradient 0.1% ammonium acetatelacetonitrile 95% to 50% in 3 min; flow 2rL/min).
MS (ES-ye) 206 kn 00 Step 3: N- {(2R)-3-[4-(3,4-Dichlorophenoxy)piperidi- 1 -yl]-2-hydroxypropyl}-5(4.
00 fluorophenyl)-1H-1,2,3-triazole4-carboxamide Prepared as Example 8. Obtained as-white solid (0.10 g).
The title compound has a pKa 6.1 (measured using Method B).
MS (APCI+ve) 508/510 'H NMR B(DMSO-d 6 1.59 1.70 (2H, 1.87 1.97 (2K 2.28 2.46(4H, 2.67 2.82 (2H, 3.24 3.41 (21, 3.81 (1H, quintet), 4.45 (I1 septet), 4.86 (11, 6.98 (11, dd), 7.26 (1H, 7.29 (2H, tt), 7.49 (11, 7.99 8.04 (2H, 8.44 (1H, t).
Example 27 N- {(2R)-3-[4-(3-Chloro-4-cyanophenoxy)piperidin-1 -yl]-2-hydroxypropyl) -2-oxo- 4-(trifluoromethyl)-2,3-dihydro- 1 H 4 F F The title compound was obtained as a white solid (0.07 g).
The title compound has pKa 6.1 (calculated using ACD).
MS (APCIve) 505/507 [M+I4H 'H NMR 8(DMSO-d 6 1.69'- 1.82 (2H, 1.95 2.06 (2H, 2.51 2.67 (41H, 2.87 -2.95 (211, 3.15-3.29 (2H, 3.80 (11, quintet), 4.65 (lH, septet), 7.10 (1H, dd), 7.30 (1H, 7.52 (11, 7.79 (1H, d).
Example 28 2 4 -(3,4-Dichlorophenoxy)piperidin-1 -yI]-2-hydroxypropyl} *-2-oxo-4.
(trifluoromethyl)-2,3-dihydro-1 00 47 0
OO
C.)1 F
F
The title compound was obtained as a white solid (0.14 g).
The title compound has pKa 6.1 (calculated using ACD).
MS (APCI+ve) 514I51l6(M+H) 00 1 H NMR S(DMSQ-d6 90 OC) 1.69 1.82 (2H, 1.92 2.06 (2H, rn), 2.52 2.75 00(4H, 2.88 3.13 (2H, 3.83 (1H, quintet), 4.50 (lH, septet), 6.98 (iN, dd), 7.23 (iH, 7.47 7.53 (1H, s).
Examl1e 29 N-{(2S-3-[4-(3-Cbloro-4-cyanophenoxy)piperidin-1 -yl]-2-hydroxypropyi}-Ninethyl-2-oxo-4-(frifluorometbyl)-2,3-dihydro-l,3-thiaz6le-5-crboxamide C1 0 QH S4 F F The title compound was obtained as a white solid (0.13 g).
The title compound has pKa 6.3 (calculated using ACD).
MS (APCI+ve) 519/521 'H NMRS(DMSO-d 6 90 0 C) 1.65 1.79 (2Km), 1.91 2.03 (211, 2.35 2.59 (411 obscured, 2.80 2.89 (2H obscured, 3.00 (3H obscured, 3.23 (1H, dd), 3.53 (1H, dd), 3.90 (11, quintet), 4.62 (1H, septet), 7.09 (111, dd), 7.30 (1H, 7.79 (21, d).
Examnie N-{(2R)-3-[4-(2,4-Dichloro-3-methylphenoxy)piperidin-1 -yi-2-hydroxypropyl}-2oxo-4-(trifluoromethyl)-2,3-dihydro-I,3-thiazole-5-carboxamide QH F
F
The title compound was obtained as a white solid (0.08 g).
The title compound bas pKa 6.1 (calculated using ACD).
MS (APCI+ve) 528/530 [M+TJ) 00 48 o 'H NMR 5(DMSO-d 6 1.74 1.87 (2H, 1.93 2.05 (211, 2.41 (311, 2.51 2.72 2.88- 2.98(211, 3.14- 3.30 (2H,i 3.82 quintet), 4.52 (11, septet), 7.07 (1H, 7.32 (11, 7.54 (1H, s).
kn 00 5 Examle 31 N- {(2R)-3-[4-(3-Chloro-4-cyanophenoxy)piperidin-1 00 isopropyl-lH-1,2,3-triazole-4-carboxamidc- 0 Step 1: Ethyl 5-isopropyl-1H-1,2,3-triazole-4-carboxylate t Prepared as Example 8 using ethyl 4-methyl-3-oxopentanoate. Used without purification.
Step 2: 5-iso-Propyl- 1H-1,2,3-triazole-4-carboxylic acid Prepared as Example 8 to yield an amber oily solid.
MS (ES+ve)156 Retention time: 0.49 min (reverse phase analytical HPLC (Hewlett Packard Series 1100); Waters "Symmetry" C8 colunm 3.5pm; 4.6 x 50mm column gradient 0.1% ammonium acetate/acetonitrile 95% to 50% in 3 min; flow 2IlJmin).
SteV 3: N- {(2R)-3-[4(3-cbloro-4-cyanophenoxy)piperidin-1-yl]-2-hydroxypropyl}-5isopropyl-1H-1,2,3-triazole-4-carboxaiide The title compound was prepared as Example 8 and obtained as a white solid (0.04 g).
The title compound has pKa 7.3 (calculated using ACD).
MS (APCI+ve) 447/449 [M+HJ' 'H NMR 8(DMSO-d 6 90 0 C) 1.25 (6H, 1.64 1.74(2H, 1.89 1.99 (211, in), 2.30 2.43 (41, 2.68 2.79 (211, 3.29 (11, dt), 3.39 (11, dt), 3.65 (11, septet), 3.78 (IH, quintet), 4.57 (1H, septet), 4.58 (1H, 7.08 (11, dd), 7.28 (11, 7.78 (11, d), 7.96 (11, s).
00 c-I 49 o Example 32 C0 C {(2S)-3-[4-(3-Chloro-4-cyaniophenoxy)piperidin- 1-yl]-2-hydroxypropyl} isopropyl-N-methyl- IH-1 ,2,3 -triazole-4-carboxamide C1 QH j N=N tfl KN .NH 00 N0 000 (0.03g).
c-I The title compound has pi~a 8.0 (calculated using ACD).
MS (APCI+ve) 46 1/463 'H NMR (DMSO-d 6 1.22 (6H, 1.54 1.70 (21H, 1.83 1.95 (2H, in), 2.19 2.39 (411, in), 2.56 -2.76 (2H, in), 3.09 (3H, 3.18 3.35 (2H, in), 3.68 (111, dd), 3.87 (1H, 4.54 (111, 7.07 (111, dd), 7.26 (111, 7.78 (111, d).
Example 33 N- {(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin- 1-yl 1-2-hydroxypropyl) -2-oxo-4- (2,2,2-trifluoroethyl)-2,3-dihydro-l Ci~~Os> H -A'
SNH
0
F
F
Step 1: Benzyl 5,5,5-trifluorc-3-oxopentanoate 3,3,3-Trifluoropropanoic acid (5 g) in dry THE (50 niL) was treated with N,Ncarbonyliimidazole (7.6 g) and the mixture was stirred at room temperature for 6 h. 2,2- Dimethyl-1,3-dioxane-4,6-dione (5.63 g) and triethylamine (5.4 niL) were added and the mixture was stirred at room temperature for 18 h. Aqueous potassium hydrogen sulphate solution (10% w/v) was added and the mixture was extracted with diethyl ether. The organic layer was separated and washed with water, then brine and dried over sodium sulphate and filtered. The solvent was concentrated in vacuo to yield a pale yellow solid.
Toluene was added, followed by benzyl alcohol. The mixture was heated at 80 'C for 6 h and was then concentrated in vactio. Purification by flash chromatography (eluent 5:95 ethyl acetate isohexane) yielded the title compound as a beig-e solid (3.1 g).
MIS (ES-ye) 259 00 c-I o 'H NMR 6(GDCl 3 3.41 (2H, 3.58 (2H, 5.19 (2H1, 7.30 7.42 (5H, mi).
Step 2: Benzyl (2E)-3-aino-5,5,5-trifluoropent-2-enoate IND Benzyl 5,5,5-trifluoro-3-oxopentanoate (2.1 g) in ethanol (15 ml.) was treated with 00 5 amninumn acetate (2 The mixture was heated at 80 OC for 18 h and was then CI concentrated in vacuo. Water and DCM were added. The organic phase was separated and 00 washed with sodium bicarbonate solution and water and then dried over sodium sulphate and filterecE The solvent was concentrated in vacuo to yield the title compound as a colourless oil (0.71 g).
Retention time: 3.34 min (reverse phase analytical HPLC (Hewlett Packard Series 1 100): Waters "Symmetry" C8 column 3.5pin; 4.6 x 50mm column gradient 0. 1% ammionium acetate/acetonitrile 95% to 50% in 3 min; flow 2mL/mun).
MS 258 [M-Hf 'H NMR B(CDCl 3 3.41 (2H1, 3.58 (211, 5.19 (2H, 7.30 7.42 (5H, in).
Step 3: Benzyl 2-oxo-4(2,2,2-trifluoroethyl)-2,3-dihydro-1 Prepared according to JlIfet. Chem. 22, 1985, 162 1-30 using benzyl (2E)-3-amino- 5,5,5-trifluoropent-2-enoate. Obtained as a pale yellow solid (0.61 g).
Retention time: 3.10 mini (reverse phase analytical HI'LC (Hewlett Packard Series 1100): Waters "Symmetry" C8 column 3.5pm; 4.6 x 50mm, column gradient 0. 1% ammonium acetate/acetonitrile 75% to 5% in 3 mini; flow 2niL/min).
MS 318 (ES+ve) [M+H]j 1H NMR B(CDCl 3 3.93 (2H1, 5.28 (2H, 7.33 7.42 (5H1, in), 9.47 (111, s).
SteR 4: 2-Oxo-4-(2,2,2-trifluoroethyl)-2,3-dihydro-1,3-thiazole-5-carboxylic acid Benzyl 2-oxo-4-(2,2,2-tritluoroethyl)-2,3-dihydro-1 ,3-thiazole-5-carboxylate (0.6 g) in ethanol was treated with 5% palladium on carbon and hydrogenated at 3 bar for 8 days. After filtration, the solvent was evaporated to yield the title compound as a colourless oil 15 g).
Retention time: 0.37 mini (reverse phase analytical HPLC (Hewlett Packard Series 11 0O):Waters "Syrnnietry" C8 column 3.5pm; 4.6 x 50mm column gradient 0.1 ammnonium acetate/acetonitrie 95% to 50% in 3 min; flow 2mL/min).
MS (ES-ye) 226 00 c-I 51 SteM 5: N- {(2R)-3-[4-(3,4-Dichlorophenoxy)piperidiii-1 -yl]-2-hydroxypropyl} -2-oxo-4- (2,2,2-trifluoroethyl)-2,3-dihydro-l,3-thiazole-5-carboxamiide IND Prepared as Example 4. Obtained as a white solid 12g).
00 The title compound has a pKa 6.6 (measured using Method B).
MS (APCI+ve) 528/530 00I 1 H NMR B(DMSO-d 6 1.56 1.68 (2H, in), 1. 86 1.96 (2H, in), 2.23 2.39 (4Hj, rn), 2.65 2.79 (2H1, in), 3.09 3.27 (2H, in), 3.73 (1Ff, quintet), 3.97 (2H1, 4.44 (1H, septet), 4.75 (111, 6.98 (1H1, dd), 7.26 (111, 7.49 (111, 7.81 (111, t).
Example 34 N- f{(2R)-3-[4-(3,4-Dichlorophenox)piperidin- 1 -yl]-2-hydroxypropyl} -2-oxo-4pyridin-2-yl-2,3-dihydro-1 d O 0 0 X~ YH 0 4 Step 1: Ethyl (2R)-3-amino-3-pyridin-2-yl acrylate Prepared as Example 33 Step 2 using ethyl 3 -oxo-3-pyridin-2-ylpropanoate to yield the title compound as a brown oil (2.5 g).
Retention time: 2.92 min (reverse phase analytical HPLC (Hewlett Packard Series 1 100): Waters "Symmnetry" C8 column 3.5 grm; 4.6 x 50Omm column gradient 0.1 ammonium acetate/acetonitrile 95% to 50% in 3 min; flow 2mL/nin).
1 H NMR 5(CDC1 3 1.32 (3H, 4.21 (2H1, 5.34 (1lH, 7.34 (111, ddd), 7.75 (2H1, td), 8.63 (111, dt).
Steu 2: Ethyl 2-oxo-4-pyridin-2-yI-2,3-dihydro-1 Prepared according to .iHet. Chem. 22, 1985, 1621-3 0.
MS (ES+ve) 251 'H NMR S(DMSO-d 6 1.08 (3H, 4.09 (2H, 7.51 (1H, ddd), 7.82 (1H, dt), 7.92 (IH, td), 8.67 (1H, dq), 12.32 (111, s).
Step 3: 2-Oxo-4-pyridin-2-y1-2,3-dihydro- 1,3-thiazole-5-carboxylic acid 00 C-I 52 o Prepared as for Example 4 to yield the title compound as a pale yellow solid.
Retention time: 0.49 min (reverse phase analytical HPLC (Hewlett Packard Series 1100): Waters "Symmetry" C8 column 3.51im; 4.6 x 50mm column gradient 0.1% ammonium acetate/acetonitrile 95% to 50% in 3 min; flow 2mJmin).
MS (ES~ve) 223 00 00 Step 4: N-{(2R)-3-[4-(3,4-Dichlorophenoxypiperidin-1-yl]-2-hydroxypropyl)-2-oxo4pyridin-2-yl-2,3-dihydro-1 Prepared as Example 15, Step 2 to yield the title compound as a white solid (0.032 g).
The title compound has pKa 7.1 (calculated using ACD).
MS (APCI+ve) 523/525tM+H)W 'H NMR B(DMSO-d 6 1.52 1.65 (2H, 1.82 1.94 (2H, 2.20 2.34 (4, 2.61 2.73 (2H, in), 3.05 3.17 (1H, in), 3.42 (1H, dt), 3.72 (11, quintet), 4.42 (11, septet), 4.83 (1H, 6.97 (lI, dd), 7.25 (1H, 7.49 (1H, 7.56 (11, dd), 7.85 (111, d), 8.04 (IH, td), 8.71 10.85 (1H, 11.96(111, s).
&@r9e N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl.-6-oxo-2- (pentafluoroethyl)-1 ,6-dihydropyridine-3-carboxamide 0 F
OH
0 Step 1: Ethyl 6-oxo-2-(pentafluoroethyl)-1,4,5,6-tetrahydropyridine-3-carboxylate A suspension of acrylamide (4.11 ethyl 4,4,5,5,5-pentafluoro-3-oxopentanoate (16.5 g) andp-toluenesulphonic acid (0.120 g) in chlorobenzene (40 mL) was sonicated for 30 minutes then heated by microwave irradiation (150W, 120 for 3 h. The reaction mixture was concentrated in vacuo and subjected to flash column chromatography (eluent 1: 3 ethyl acetate/isohexane) to yield a colourless solid (0.697 g).
MS (ES-ye) 286 [M-11 00 53 1 1 NMR 8(CDCl 3 7.1.3 IMi', 4.25 J= 7.2 Hz, 2H), 2.79 2.73 (mn, 2H), 2.62 -2.57 (in, 2H), 1.30 J 7.1 Hiz, 3H{).
Step 2: tthyl. 6-oxo-2-(pentafiuoroethyl)-1 ,6-dihydxopyridine-3-carboxylate suspension of ethyl 6 -oxo-2(pentafuoro ethyl)- 1,4,5,6tehydropyridine-3 tn carboxylate (0.690 g) and N-broinosuccinimide (0.427 g) in carbon tetrachloride (5 niL) 00 C*Nwas heated at 80 *C for 20 h1 The reaction mixture was concentrated Mn vacuo and
(N
N0 subjected to flash column chromatography (eluent. I 3 ethyl acetate/isohexane) to yield a colourless solid (0.30 g).
MS (ES-ye) 284 [M-H]l 'H NMR B(CDCl 3 1.36 (3H, 4.37 (2H, 6.93 (1H, 7.90 (1H, d).
Slen3: 6-Oxo-2-(oentafluoroethy1)-1,6-dihydropyridine-3-carboxylic acid A suspension of ethyl 6 -oxo-2-(pentafluoroethyl)-1,6-dihydropyridine-3 carboxylate (0.300 g) in concentrated hydrochloric acid (10 niL) was heated at reflux for h. The reaction mixture was cooled and a colourless solid filtered off (0.30 g).
MS (JES-ve) 256 'H NMvR 8(DMSO-d 6 6.98 (1WH, 8.04 (iH, 12.03 (1W, s).
Step4 N-{(2R)-3-L4-(3,4-Dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropy}-6-oxo-2- (pentafluoroethyl)-1 ,6-dibydropyridine-3-carboxamide A stirred solution of 6-x--pnalooty)16dhdoyiie3cioyi acid 105 g) in thionyl chloride (5 mL) was heated at reflux for 3 h. Thionyl chloride was removed from the cooled solution in vacuo. The residue was dissolved in THEO (4 inL) and this solution was added drop wise at room temperature to a solution of (2,R)-.1-amino-3-[4- (3,4-dichlorophenoxy)piperidin-l -yl]propan-2-ol (0.130 g) and triethylamine (0.4 niL) in DCM (5 mL) before stirring overnight. The reaction mixture was concentrated in vacuo and redissolved in 9 1 acetonitrilelwater (4 m.L) before subjecting to RPHPLC (gradient 0.1% ammnonium acetate/acetonitrile, 95% to 50%) to yield the title compound as a white solid (125mg).
The title compound has pKa 6.3 (calculated using ACD).
MS (ES+ve) 5581560 NMIR 6(CD 3 OD) 1.69 1.79 (2H, in), 1.90 1.99 (2H, in), 2.48 2.60 (4H, rn), 00 cl 54 2.81 2.91 (2H, 3.26 (11, dd), 3.35 (111, dd), 3.87 3.93 (114, 4.34 4.39 (lH, i), 6.77 (1H, 6.81 (11, dd), 7.02 (1W, 7.29 7.64 (IH, d).
Exaple 36 tn 5 N- {(2R)-3-[4-(3,4-Dichlorophenoxypiperidin1 00 (methylthio)-lH-1, 2 ,3-triazole-4-carboxamide 00 OH N=N N
NH
0 To a stirred suspension of 5-(methylthio)-lH-,2,3-triazole-4-carboxylic acid [J Chem. Soc. Perkin. Trans. 1 1982, 627] (0.085 g) in DOM (2 mL) was added oxalyl chloride (0.09 ml) then DMF (1 drop). T he,reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo and the residue was dissolved in THF (2 nL) and this solution was added dropwise at room temperature to a solution of 2 R)-l-amino-3-[4-(3,4-dichlorophenoxypiperidin yl]propan-2-ol (0.169 g) and Iriethylamine (0.22 ml) in DCM (5 mL). After being stirred for 1 h the reaction mixture was concentrated in vacuo and redissolved in methanol (4 irL) before being subjected to RPHPLC (gradient 0.1% anmonium acetate/acetonitrile 95% to 50%) to yield a white solid (0.091 g).
The title compound has a pKa 5.5 (measured using Method B).
MS (ES+ve) 460/462 'H NMR 5(CD 3 OD) 1.76 1.88 (2H, 1.93 2.06 (211, 2.45 (3H, 2.63 2.77 (4H, 2.92- 3.04 (2H, in), 3.35 (2H, 3.91 3.99 (1H, in), 4.38 4.46 (1H, i), 6.82 (11, dd), 7.05 (1H, 7.30 (1W, d).
Examnle37 N- 2 R)-3-[4-(3,4-Dicblorophenoxy)piperidin-1 -yl]-2-hydroxypropyl}-2-oxo-4- (trifluoromethyl)-2,3-dihydro-l 0
'JQ
0 Y iQH 0F
F
00 C Ethyl 2-oxo-4-(trifluoromethyl)-2,3-dihydro-1,3-oxazole-5-carboxylate (0.3 g) [EP 0 0 027 020 Al] was treated with a solution of lithium hydroxide dissolved in 3 :1 THF/ water (6 mL), and heated at 50 OC for 1 h. The reaction mixture was partitioned between water (10 mL) and tthyl acetate (10 mL). The aqueous phase was acidified to pH 3 using ,D 5 dilute hydrochloric acid, followed by extraction with ethyl acetate (3 x 10 mL). The 0 organics were combined and washed with water (2 x 10 mL) and brine (10 mL), then dried S(Na 2
SO
4 filtered, and concentrated in vacuo to leave the acid as an off white solid (0.175 00 Purification was carried out on amine resin by flushing with methanol to remove 0impurities, followed by 5 formic acid in methanol to isolate the product.
A stirred solution of 2-oxo-4-(trifluoromethyl)-2,3-dihydro-1,3-oxazole-5carboxylic acid (0.032 g) in thionyl chloride (4 mL) was heated at reflux for 2 h. Excess thionyl chloride was removed from the cooled solution in vacuo. The residue was Sdissolved in THF (2 mL) and this solution was added dropwise at room temperature to a solution of (2R)-l-amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol (0.051 g) and triethylamine (0.24 mL) in DCM (1 mL) before being stirred overnight The reaction mixture was concentrated in vacuo, and the residue was redissolved in acetonitrile containing 2-3 drops each of water, methanol and acetic acid before it was subjected to RPHPLC Novapak (gradient 0.1 ammonium acetate/acetonitrile 95 to followed by normal phase elution with 3/17 mixture of 7 N NH 3 in methanol/ dichloromethane. This yielded the desired product as a yellow solid (0.016 g).
The title compound has pKa 5.8 (calculated using ACD).
MS (ES-ve) 498/496 'H NMR 6(CD 3 0D) 1.77 1H), 2.07 1H), 2.94 2.91 1H), 3.02 2.98 (m, 1H), 3.18 3.06 3H), 3.42 3.36 3H), 3.74 3.69 1H), 4.62 (quintet, 1H), 5.25 1H), 5.43 1H), 5.53 1H), 5.70 1H), 6.95 (dd, 2.8 Hz, 1H), 7.18 1H), 7.40 1H).
Example 38 N- {(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-5- (trifluoromethyl)-lH-1,2,3-triazole-4-carboxamide.
00 56
OH=N
N o ciF 0
FF
Ste 1: 5-(Trifluoromethyl)-1H-1,2,3-triazole-4-caboxylic acid.
kn Ethyl 5-(trifiuoromethyl)-IH-1,2,3-triazole-4-aboxylate (0.312 g) was stirred in 00 aqueous N sodium hydroxide (3.8 nL) and heated under reflux for 90 min. The cooled cI 5 solution was acidified with aqueous hydrochloric acid and extracted with ethyl acetate. The 00 extracts were washed with brine then dried and evaporated to leave a colourless solid c-I (0.226 g).
MS (ES-ye) 180 [M-HT- Step 2: N(2p)-3-[-(3,4-ichlpiophenoxy)piperidi-lyl]-2-hydroxypropyl5- (trifiuoromethyl)-I-13-triazle4-caboxaide.
Prepared by the method of Example 8 to give the title compound (0.113 g).
The title compound has a pKa 4.0 (measured using Method B).
MS (APCI+ve) 482/484/486 [M+H] is 1 H NMR 8(CD 3 OD) 2.04 (4H, 2.99 (111, 3.13 (31, 3.32 (211, 3.39 (2H, 4.10 (1H, 4.58 (IH, 6.88 (lH, dd), 7.13 (1H, 7.34 (lH, d).
Exaple 39 N-(2R)-3-[4-(3,4-Dichloropheoxy)piperidi-1-yl]-2-hydroxypropyl [methyl(methyl sulfonyl)amino]-lH-1,2,3-triazole-4-carboxamide.
C1 9H N=IEI NH
Q~J~LNH
.4 0
Y,
0 Step 1: Ethyl 5-amino-l-(4-methoxybezyl)-IH-1l,2,3-triazole4-carboxylate Ethyl cyanoacetate (1.96 nL) was added to a solution of sodium ethoxide, prepared from sodium (0.423 g) and ethanol (45 miL), and the solution was stirred for 30 min. A solution of 4-methoxybenzylazide (3.0 g) in ethanol (5 mL) was added dropwise and the mixture was heated under reflux for 5 h. The cooled mixture was poured into water aad acidified with dilute hydrochloric acid then extracted with ethyl acetate. The extracts were 06
O
c 57 O washed with water, brine and evaporated. Purification by flash chromatography (ethyl acetate/ dichloromethane 1:9 then 15:85) gave the product as a pale yellow solid (0.85 g).
MS (APCI-ve) 275 [M-H]
ID
00 5 Step 2: l-(4-Methoxybenzyl)-5-[(methylsulfonyl)amino]- H-1,2,3-triazole-4-carboxylic acid oo Ethyl 5-amino-l-(4-methoxybenzyl)-lH-1,2,3-triazole-4-carboxylate (0.85 g) and 0 methane sulphonyl chloride (0.72 mL) were stirred in pyridine (20 mL) for 4 d. Further methane sulphonyl chloride (0.72 mL) was added and stirring continued for 24 h. Further methane sulphonyl chloride (0.5 mL) was added and stirring continued for 24 h. The mixture was concentrated in vacuo. The residue was suspended in dilute hydrochloric acid and extracted with ethyl acetate. The extracts were washed with dilute hydrochloric acid and water then evaporated. The residue was taken up in ethanol (70 mL) and 2 M sodium.:-. hydroxide solution (70 mL) and stirred for 18h. The mixture was concentrated to about half volume and acidified with dilute hydrochloric acid. The mixture was extracted with ethyl acetate and the extracts were washed with water and brine, then dried and evaporated to leave a white solid (0.90 g).
'H NMR 8(CD30D) 3.15 (3H, 3.79 (3H, 5.63 (2H, 6.92 (2H, 7.32 (2H, d).
Step 3: Methyl 1-(4-methoxybenzyl)-5-[methyl(methylsulfonyl)amino]-lH-1,2,3-triazole- 4-carboxylate 1-(4-Methoxybenzyl)-5-[(methylsulfonyl)amino]-IH-1,2,3-triazole-4-carboxylic acid (0.9 g) and potassium carbonate (1.15 g) were stirred in dry DMF (10 mL). Methyl iodide (0.83 mL) was added and the mixture was stirred for 5 h. The mixture was poured onto water and extracted with ethyl acetate. The extracts were washed with dilute hydrochloric acid, water and brine then dried and evaporated. Purification by flash chromatography (ethyl acetate/ DCM 1:9) afforded the sub-titled compound as a brown solid (0.54 g).
MS (APCI+ve) 355 [M+H] Step 4: Methyl 5-[methyl(methylsulfonyl)amino]-lH-1,2,3-triazole-4-carboxylate 00 58 C1 Methyl 1 -(4-methoxybenzyl)*5-[methyl(methylsulfonyl)amino]-1H1,2,3triazole O 4-carboxylate (0.54 g) was stirred in trifluoroacetic acid (5 mL) at 60 *C for 6 h. The mixture was evaporated and the residue was co-evaporated with toluene. Purification by flash chromatoraphy (1:49 methanol! DCM) gave the subtitle compound as a gum (036 g).
MS (APCI+ve) 235 [M+Hrfl kn 00 SteP 5: 5-[Methyl(methylsulfonyl)amino]-lH-l ,2,3-tiazole.4-carboxylic acid 00 Methyl 5-[methyl(methylsulfonyl)amino]-lH-1,2,3-triazole-carboxylate (0.36 g) was stirred in THF (5 mL) with 2 N aqueous sodium hydroxide solution (1.7 niL) for 18 h.
The mixture was concentrated in vacuo. To the aqueous residue was added dilute acetic acid and this was extracted with ethyl acetate (2 x 15 mL). The extracts were washed with water and brine then dried and evaporated to leave the subtitle compound (0.07 g).
MS (APCI-ve)219 [M-H Step 6: N-{(2R)-3-[4-(3,4-dicllorophenoxy)piperidin-l-yl]-2-hydroxypropyl}..5- [methyl(methylsulfonyl)amino]-1H-1 ,2,3-triazole-4-carboxamjde.
Prepared using 5-[methyl(methylsufonyl)amino-H-1,2,3-riazol1e.4carboxylc acid (0.07 g) by the method of Example 8 to give the title compound (0.25 g).
The title compound has pKa 4.2 (calculated using AC)).
MS (APCI-ve) 519 [M-fff 'HNMR S(CD 3 OD) 1.95-2.06 (2H, in), 2.08-2.22 (2H, 2.94 3.01 (1H, 3.06 (3H, 3.07-3.15 (11, 3.18-3.29 (311, in), 3.33 3.49 (2H, 4.12 (11, 4.60 (11, 6.94 (1H, dd), 7.18 (1H, 7.41 (IH, d).
Example N-{(2R)-3-[4-(3-Chloro-4-cyano-2-methylphenoxy)piperidin-1-yl-2hydroxypropyl) -2-oxo-4-(trifluoromethyl)-2,3-dibydro-l 3 C1 N 0 Y>OH S4 Nf J
NH
ij F F
F
Step i: 2-Chloro4-hydroxy-3-methylbenzonitrile 00 ci stirred solution -of 4-bromo-3-ehloro-2-methylphenol(047gzncyid (0.27 1 and tetrakis[triphenylphosphine] palladium (0.056 g) in N-methyl-2pyrrolidinone (5 niL) was heated under microwave irradiation (150 W) at 130 0 C for min. The reaction mixture was filtered through anhydrous magnesium sulfate, partitioned IND 5 between 1 :2 ethyl acetate/ diethyl ether (15 mL) and water (15 mL). The aqueous phase 00 was re-extracted with 1 :2 ethyl acetate! diethyl ether (2 x 15 inL). The organics were combined, washed with water (2 x 20 mL), dried over anhydrous magnesium sulfate, 00 filtered and concentrated in vacuio. The compound was purified by column chromatography using 1 9 ethyl acetate! iso-hexane as eluent, to give the desired product as a peach coloured solid (174 mg, 54 Retention time: 1.60 min (reverse phase analytical HPLC (Hewlett Packard Series 1100): Waters "Symmetry" C8 column 3.Spm; 4.6 x 50mm column gradient 0.1% -ammnonium acetate/acetonifrile 75% to 5% in 3 min; flow 2mL/min).
MS (ES-ye) 166/168 [M-11]+ 'H NMR 8 (CD 3 OD) 2.27 3H), 6.82 8.5 Hz, 1ff), 7.44 J= 8.8 Hz, 1H).
Step 2: tert-Butyl 4-( 3 -chloro 4 -cyano- 2 -methylphenoxy)piperidine-1-carboxylate Prepared according to method in patent WO 0220484 Al.
Retention time: 2.83 min (reverse phase analytical HPLC (Hewlett Packard Series 1100): Waters "Symmetry" C8 column 3.Spm; 4.6 x 50mm column gradient 0. 1% amnmonium acetate/acetonitrile 75% to 5% in 3 min; flow 2znL/iin).
'H NMR B(CDCl 3 1.48 9H1), 1.86 1.75 (mn, 2H), 1.99 1.89 (mn, 2H), 2.32 (s, 3H), 3.51 3.42 (mn, 2H), 3.65 3.57 2H), 4.64 4.57 (in, Mii), 6.80 8.7 Hz, 1H) ,7.49 8.7 Hz, lH) Step) 3: 2-Chloro-3-inethyl-4-(piperidin-4-yloxy)benzonitrile Prepared according to Preparation 1, Step 2.
Retention time: 1.17 min (reverse phase analytical HPLC (Hewlett Packard Series 1100): Waters "Symmetry" C8 column 3.5p.m; 4.6 x 50mm column gradient 0.1% armnonium acetate/acetoitrile 75% to 5% in 3 min; flow 2mL/min).
MS (ES+ve) 251/253 00 060 'H NMR 8(CDCI 3 1.80 1.70 2H), 2.06 1.96 21), 2.32 3H), 2.83 2.75 21), 3.18 3.09 2H), 4.54 4.47 1f), 6.79 J= 8.9 Hz, 1H), 7.47 J =8.7 Hz, 111).
5 SteR 4: 4-(fI -[(2R)-3-Aino-2-hydroxypropyl]piperidin-4-yl oxy)-2-chloro-3- 00 metbylbeuzonitrile 00 Prepared according to Preparation 1, Step 3.
Retention time: 1.20 min (reverse phase analytical HPLC (HewlettPackard Series 1100): Waters "Symmetry" C8 column 3.5pan; 4.6 x 50mm column gradient 0.1% ammonium acetate/acetonitrile 75% to 5% in 3 min; flow 2mUmin).
MS (ES+ve) 324/326 'H NMR B(CDC 3 1.29 1.22 2H), 1.94 1.81 21, 2.08 1.95 21), 2.31 2.31 2.46 2.33 31), 2.67- 2.59 (in, 3H), 2.90 -2.80 21), 3.73 3.66 11), 4.51 4.44 (in, 11), 6.79 J= 8.8 Hz, 11), 7.47 J= 8.7 Hz, 1H).
Sten 5: N- {(2R)-3-[4-(3-Choro4-ryano-2-methylphenoxy)piperidin-1-yly2 hydroxypropyl}-2-oxo-4-(trifluoroethyI)-2,3-dihydro-1 Prepared according to method for Example 4.
Retention time: 1.18 min (reverse phase analytical HPLC (Hewlett Packard Series 1100): Waters "Symmetry" C8 column 3.5un; 4.6 x 50mm column gradient 0.1% ammonium acetate/acetonitrile 75% to 5% in 3 min; flow 2rnL/in).
The title compound has a pKa of 4.7 (measured using Method B).and pKa 6.1 (calculated using AC)).
MS (ES+ve) 519/521 (ES-ye) 517/519 'H NMR 8 (DMSO-d 6 1.81 1.91 2H), 2.02 2.10 2.33 311), 2.54 -2.70 4H), 2.88 2.95 21), 3.24 3.31 11), 3.34 3.41 (in, 11), 3.87 (quintet, 1H), 4.63 4.69 11), 7.17 11H), 7.54 7.64 111), 7.68 IH).
Examnle 41 N- {(2R)-3-[4-(3-Chloro-4-cyanophenoxy)piperidin- 1 -yl]-2-hydroxypropyl} (trifluoromethyl)- 1H-1 ,2,3-triazole-4-carboxanide 00. 61 PH N= o NH F C) F Prepared by the method of Example 31 to give the title compound (0.64 g).
IN The title compound has pKa 2.1 (calculated using ACD).
00 MS (APCI+ve) 4731475 N 5 1H NMR 6(CD 3 OD) 2.39-2.67 (4H1, in), 3.44 (11, in), 3.55-3.90 (6H1, in), 3.84 (lH, 0n) 7.45 (111, dd), 7.65 (1K1 8.08 (111, d).
Example 42 2-Chloro-5-[({(2R)-3-[4-(3,4-dichloro-2-inethylphenoxy)piperidin-1-yl]-2hydroxypropyl} amino)carbonyl~benzoic acid 01 Or H I1 cl 0 0 H Step 1: 3-tert-Butyl 1-methyl 4-chloroisophthalate tert-Butyl 5-bromo-2-chlorobenzoate (1.9 g) (W02003095430) was dissolved in methanol (1 8mI) with N,NV-diisopropylethylamine (2 inL) and dichlorobis(triplienylphosphine)-palladiumnll (0.134 The mixture was carbonylated at IC for 12 ii. The cooled solution was evaporated and purified by flash chromatography, eluting with 5:95 ethyl acetate/isohexane, to yield the subtitle compound as a colourless oil (0.67 g).
'HI NMR 8(GDCl 3 1.62 (9H1, 3.94 (3H1, 7.49 (1H1, dd), 8.02 (1H1, dd), 8.35 (1H1, d).
Step 2: 3-(tert-Butoxycarbonyl)-4-chlorobenzoic acid 3-tert-Butyl 1-methyl 4-chloroisophthalate (0.37 g) in TiHF (5 mL) was treated with lithium hydroxide 17 g) in water (5 mnL) and the mixture was stirred for 18 h. The solvent was evaporated. Water and ethyl acetate were added. The aqueous extract Nvas separated and acidified with dilute hydrochloric acid. The product was extracted into ethyl 00 c-I 62 o acetate. The solution was dried over sodium sulphate, filtered and the solvent was evaporated to yield the subtitle compound as a white solid (0.32 g).
Retention time: 1.98 min (reverse phase analytical HPLC (Hewlett Packard Series 1100): Waters "Symmetry" C8 column 3.Spzn; 4.6 x 50mm column gradient 0.1% 5 animoniumn acetate/acetonitrile 95% to 50% in 3 min; flow 2mL/min).
00 MS (ES-ye) 255 [M-H]l 'H NMR B(DMSO-d 6 1.56 (9Hf, 7.69 (1Hf, 8.03 (111, dd), 8.18 (1 H, d).
00 Sten3: tert-Butyl 2-chloro-5-[(((2R)-3-E4-(3,4-dichloro-2-methylphenoxy)piperidm1i-yl-* 2-hydroxypropyl~amino)carbonyljbenzoate Prepared as for Example 15, Step 2 and the sub-titled compound was obtained as a colourless oil (0.14 g).
Retention time: 2.93. min (reverse phase analytical IIPLC (Hewlett Packard Series 1100): Waters "Symmetry" C8 column 3.5pmn; 4.6 x 50mm column gradient 0. 1% anmoniumn acetate/acetonitrile 75% to 5% in 3 min; flow 2mL/min).
MS (ES+ve) 571 [M+Hr+ Step4: 2-Chloro-5-[( ((2R)-3-[4-(3,4-dchloro-2-methylphenoxy)piperdinl..y1J-2 hydroxypropyl)aniino)carbonyl]benzoic acid tert-Butyl 2-cbloro-5-[( 2 R)-3-[4-(3,4-dichloro-2-methylphenoxy)piperidin..l..J 2-hydroxypropyl) anino)carbonyljbenzoate 14 g) in DCM (5 mL) was treated with trifluoroacetic acid (1.5 mL) and the mixture was stirred for 1.5 h. The solvent was evaporated. The product was purified by RPHPLC (Symmetry, 0.1% ammoniumi acetate/acetonitrile) to yield the title compound as a white solid.(0.05g).
The title compound has a measured pKa 2.3, and a calculated pKa 2.6 (calculated using ACD).
MS (AFGI-ve) 5 13/5 17[M-H]- 'H NMR 8(CD 3 OD +NaOD) 1.79 -1.91 (2Hf, in), 1.98 2.09 (2Hf, in), 2.34 (3Hf, s), 2.47 2.58 (2H, mn), 2.52 (2H, 2.75 2.87 (2Hf, mn), 3.43'(1H, dd), 3.53 (1ff, dd), 4.02 (1ff, quintet), 4.44 4.53 (1ff, mn), 6.95 (1H, 7.31 (1ff, 7.49 (1ff, 7.77 (lHL dd), 7.96 (1 H, d).
Example 43 00 6 N4-Chloro-3-[( {(2R)-3-[4-(3,4-dichloro-2-metbylphenoxy)piperidin1yl..2hydroxypropy!} amino)carbonylbenzoic acid cl N&-0
QH
IND 0 OH0 kn Step 1: Methyl4-chloro- 3 -[({(2R)-3-[4-(3,4-dichloro-2-methylphenoxy)piperidin..1-y}.2 00 hydroxypropyl~amino)carbonyl]benzoate 00 Prepared as for Example 15, Step 2 using 2 acid (FR2842805) and 2 R)-l-amino- 3 4 -(3,4-dichloro-2-methylphenoxy)pjpeidjn..1.
yl]propan-2-ol and was obtained as a colourless oil (0.1 g).
Retention time: 2.42 mini (reverse phase analytical KPLC (Hewlett Packard Series 1100): Waters "Synimetr'C8 column 3.5pm; 4.6 x 50mm column gradient 0. 1% ammonium acetite/acetonitrile 75% to 5% in 3 mini; flow 2mliiin).
MS (ES-ve) 5298531 [M-H1 Step 2: 4 -Chloro- 3 2 R)-3-[4-(3,4-dichloro-2-metbylphenoxy)piperiin..1y].2 hydroxypropyl) amino)carbonyljbenzoic acid Prepared as for Example 23, Step 3 and obtained as white solid (0.022 g).
The title compound has pKa 3.7 (calculated using ACD).
MS (APCJ-ve) 5l3/517[M-Hi] 'H NMR S(CD 3 OD) 1.78 1.89 (2H1, 1.97 2.08 (2H1, in), 2.34 (3H1, 2.47 2.62 (4H1, mn), 2.79 2.90 (2H1, in), 3.49 (2H, ddd), 4.03 (111, quintet), 4.46 (lH, septet), 6.95 (IH, 7.30 (lH, 7.48 (1H, 8.00 (111, dd), 8.06 (11, d).
ExaMple 44 4-Chloro-3-[2-(f 2
R)-
3 4 4 -dichloro-2-methylphenoxy)piprilin-1 -yl]-2hydroxypropyl) araino)-2-oxoethoxy]benzoic acid Step-I: Methyl 3 2 -ter-t-butoxy-2-oxoethoxy)-4-chlorobenzoate 00 c-I 64 o Methyl 4-chloro-3-hydroxybenzoate [Chem. Phann. Bull. 1994,42(1 1),2365-9] (0.73 caesium carbonate (1.27 g) and tert butyibromoacetate (0.58 mLs) in DMI (6 mL) were heated and stirred at 60 *C for 3 h. Water was added and the product was extracted into ethyl acetate. The extracts were dried over sodium sulphate, filtered and the solvent 00 5 was evaporated. The resulting oil was purified by flash chromatography, using 1: 10 ethyl c-I acetate/isobexane as eluent, to yield the subtitle compound as a colourless, oil (1.25 g).
00 'H NMR B(CDCl 3 1.49 (9H, 3.91 (3H, 4.66 (2H, 7.45 (111, 7.48 (1H, 7.62 (KH dd).
Stel? 2: [2-Chloro-5-(methoxycarbonyl)phenoxy]acetic acid Prepared as Example 42 Step 4 to yield the subtitle compound as an off white solid 18 g).
NMR 8(DMSO-d 6 3.86 (3H, 4.93 (2H, 7.48 (111, 7.56 (11, dd~j 7.62~ (1H, 13.21 (1H, s).
MS (ES-ye) 243 [M-H] Step3: Methyl 4-chloro-3-[2-({(2R)-3-[4-(3,4-dichloro-2-methylphenoxy)piperidin-1 -yl].
2-hydroxypropyl~amino)-2-oxoethoxy]belzoate Prepared as for Example 15 Step 2 using phenoxy] acetic acid and (2R)-1 -amino-3-[4(3,--dichloro-2-methylphenoxy)piperidin-1 yl~propan-2-ol to yield the subtitle compound as a colourless oil (0.084 g).
MS (E-S+ve) 561/3 Retention time: 2.58 mnin (reverse phase analytical HPLC (Hewlett Packard Series 1 100): Waters "Symmetry" C8 column 3.5gm; 4.6 x 50mm, column gradient 0.1% ammnonium acetate/acetonitrile 75% to 5% in 3 min; flow 2mL/min).
Step.4: 4-Chloro-3-[2-( {(2R)-3-[4-(3,4-dichloro-2-methylphenoxy)piperidin- 1-yl]-2hydroxypropyll amino)-2-oxoethoxy]benzoic acid Prepared as for Example 23, Step 3. The title compound was obtained as a white solid (0.02 g).
The title compound has pKa 3.8 (calculated using ACD).
MS (APCI-ve) 545/547[M-1-1] 00 'HNMR 5(CD 3 0D) 1.98 2.13 (211, 2.16 2.31 (2H,nm), 2.34 (3H, 2.94 3.11 (211, 3.15 -3.26 (21, 3.34 (2H, 3.40 (211, 4.10- 4.17 (11, 4.64 o 4.70 (1H, 4.71 (2H, 6.99 (1H, 7.32 (11H, 7.41 (11, 7.58 (11H, dd), 7.59 (1H, s).
IN Example 00 02-Chloro-5-[({(2R)3-[4-(3,4-dichoro-2-methyphenoxy)piperidin-1.yl]2 hydroxypropyl} amino)carbonyl]phenoxy acetic acid 00 Y O'COOH SteR 1: 3-!(2-tert-Butoxy- 2-oxoethoxy)-4-cblorobenzoic acid Methyl 3 2 -tert-butoxy-2-oxoethoxy)4-chlorobenzoate (0.7g) in 9:1 tert butanol:water was subjected to Antarctica B lipase for 6 d. Filtration and evaporation of the solvent yielded the subtitle compound as an off-white solid (0.6 g).
MS (ES-ye) 285 'H NR 8(DMSO-d 6 1.42 (9H, 4.88 (2H, 7.45 (11, 7.54 (1H, dd), 7.58 (11, d).
Step 2: tert-Butyl 2 -cloro-5-[({(2R)-3-(4-(3,4-dichloro-2-methylphenoxy)pip iciin-1 yl]-2-hydroxypropyl} amino)carbonyllphenoxy} acetate Prepared as for Example 15, Step 2 using 3 -(2-tert-butoxy-2-oxoethoxy)-4chlorobenzoic acid and (2R)-l-amino-3-[-(3,4-dichloro-2-methylphenoxypiper iyljpropan-2-ol to yield the subtitle compound as a colourless oil (0.14 g).
MS (ES+ve) 603/5 Retention time: 2.98 min (reverse phase analytical HPLC (Hewlett Packard Series 1100): Waters "Symmetry" CS column 3.5pm; 4.6 x 50mm column gradient 0.1% ammonium acetatefacetonitrile 75% to 5% in 3 min; flow 2mL/min).
Step 3: 2 -Chloro-5-[({( 2 R)-3-[4-(3,4-dichloro-2-methylphenoxy)piperidin- I-yl]-2hydroxypropyl) amino)carbonyl]phenoxy) acetic acid Prepared as Example 42 Step 4 to yield the title compound as a white solid (0.085 00 66 o The title compound has pKa 3.0 (calculated using ACD).
MS (APCI-ve) 543/547[M-H11 'H NMR 8(CD30D +NaOD) 1.74 1.86 (2H, in), 1.95 2.05 (2H, 2.31 (3H, s), 2.41 2.52 (4H, 2.74 2.84 (2Hnim), 3.32 3.38 (11, in), 3.50 (iN, dd), 3.98 (i, quintet), 4.42 (fif, septet), 4.54 (2H, 6.91 (1H, 7.27 (1H, 7.37 (1H, dd), 7.38 (1H, 7.44 (11, d).
00 Example 46 3-[2-({(2R)-3-[4-(3,4-Dichloro-2-iethylphenoxy)piperidin-1-yl]-2hydroxypropyl} amino)-2-oxoetboxy]benzoic acid 0 Step 1: Methyl 3-[2-({(2R)-3-[4-(3,4-dichloro-2-methylphenoxy)piperidin-l-yl-2hydroxypropyl} amino)-2-oxoethoxyjbenzoate Prepared as for Example 15, Step 2 using [3-(methoxycarbonyl)phenoxy]acetic acid lAsian Journal of Chemistry 1992,4(4),920-3] and (2R)-l-amino-3-[4-(3,4-dichloro-2nethylphenoxy)piperidin-l-yl]propan-2-ol to yield the subtitle compound as a pale yellow oil 11 g).
MS (ES+ve) 525/527 [M+H+ Retention time: 2.35 min (reverse phase analytical HPLC (Hewlett Packard Series 1100): Waters "Symmetry" C8 column 3.511m; 4.6 x 50mm column gradient 0.1% ammonium acetate/acetonitrile 75% to 5% in 3 min; flow 2mL/min).
Step 2: {(2R)-3-[4-(3,4-Dichloro-2-methylphenoxy)piperidinl -yl]-2hydroxypropyl) amino)-2-oxoethoxy]benzoic acid Prepared as for Example 23, Step 3. The title compound was obtained as a white solid (0.049 g).
The title compound has a measured pKa 2.6 and a calculated pKa 4.0 (calculated using ACD).
MS (APCI-ve) 509/511 00 67 'H NMR 5(CD 3 OD NaOD) 1.73 1.85 (2H, 1.94 2.03 (2H, 2.30(311, s), 2.33 2.47 (4H, 2.68 2.78 (21, 3.32 3.44 (211, 3.90 (JH, quintet), 4:37 o 4.46 (11, 4.57 (2H, 6.92 (1H, 7.04 7.08 (11, 7.24 734 (21, 7.56 7.61 (2H, m).
IN Example 47 2
R)-
3 4 -(3,4Dichloro-2-methylphenoxy)piperdin-1.y].2hydroxypropyl) anino)carbonyl]phenoxy) acetic acid 00 6%N -COOH Step 1: tert-Butyl {3-[(((2R-3-[4-(34-dichro-2-methylphenoxy i -ylj-, hydroxypropyljamino)carbonyl]phenoxy) acetate Prepared as for Example 15 Step 2 using 3 2 -tert-butoxy-2-oxoethoxy)benzoic acid [WO 00/78317 Al] and (2R)-l -amino- 3 4 -(3,4-dichloro-2-methylphenoxy)piperid in 1 -yl]propan-2-ol to yield the subtitle compound as a white solid (0.11 g).
MS (ES+ve) 567/569 [M+HJ+ Retention time: 2.65 min (reverse phase analytical HPLC (Hewlett Packard Series 1100): Waters "Syimmetry" C8 column 3.5 pmi 4.6 x 50mm column gradient 0.1% ammonium acetate/acetonitrile 75% to 5% in 3 min; flow 2m/min).
!0 Step 2: 3 2
R)-
3 4 -(3,4-Dichloro-2-methylphenoxy)piperidin-1.yl]2hydroxypropyl) amino)carbonyl]phenoxy acetic acid Prepared as Example 42, Step 4 to yield the title compound as a white solid (0.063 g).
The title compound has pKa 3.1 (calculated using ACD).
MS (APCI+ve) 511/513 'H NMR 5(CD 3 OD NaOD) 1.75 1.87 (214, 1.96 2.05 (211, 2.31 (311, s), 2.42 -2.54 (4H, 2.75 2.85 (211, 3.37 (IH, dd), 3.50 (11, dd), 3.99 (1 H, quintet), 4.47 (3H, 6.91 (11, 7.08 7.12 (111, 7.27 (11, dd), 7.32 7.40 (311, i).
Example 48 Pharmacological Analysis: Calcium flux [Ca 21i assay 00 68 o Human eosinophils Human easinophils were isolated from EDTA anticoagulated peripheral blood as previously described Hansel et al., J inynunoL. Methods, 1991, 145 105-110). The cells INO were resuspended (5x1 0 6 mit-) and loaded with 5pM FLUO-3/M Plutonic F 127 00 5 2.2 p./mi (Molecular Probes) in low potassium solution (LKS; NaC1 11 8mM, MgSO 4 0.8mM, glucose 5.5mM, Na 2
CO
3 8.5mM, KCl 5mM, HEPES 20M, CaCl2 1.8mM, BSA 00 pH 7.4) for one hour at room temperature. After loading, cells were centifuged at 200g for 5min and resuspended in LKS at 2.5x10 6 mT 1 The cells were then tranferred to 96 well FLIPr plates (Poly-D-Lysine plates from Becton Dickinson pre-incubated with 5pM fibronectin for two h) at 25 p1/well. The plate was centrifuged at 200g for 5min and the cells were washed twice with LKS (200p1l; room temperature).
A compound of the Examples was pre-dissolved in DMSO and added to a final concenitration of 0:16/'(WVf) DMS6. A~says were initiated by the addition of an Aso r; concentration of eotaxin and the transient increase in fluo-3 fluorescence Oft 490nm and ]Em 520n) monitored using a FL]PR (Fluorametric; Imaging Plate Reader, Molecular Devices, Sunnyvale, Compounds of the Examples were found to be antagonists if the* increase in fluorescence induced by eotaxin (a selective CCR3 agonist) was inhibited in a concentration dependent umner. The concentration of antagonist required to inhibit the fluorescence by 50% can be used to determine the 1050 for the antagonist at the CCR3 receptor.
Example 49 Human eosinophil chernotaxis Human cosinophils were isolated from EDTA anticoagulated peripheral blood as previously described (Hansel et al., J Immunol. Methods, 1991, 145. 1054.10). The cells were resuspended at l0X10 6 MI in RPi~ containing 200 ITJ/ml penicillin, 200 [pg/nil streptomnycin sulfate and supplemented with 10% HIFCS, at room temperature.
Eosinophils (700 gl) were pre-incubated for 15 muns at 370 C with 7 p.1 of either vehicle or compound (100x required final concentration in 10% DMSO). The chemotaxis plate (ChemoTx, 3pmr pore, Neuroprobe) was loaded by adding 28p1 of a concentration of eotaxin 0. 1 to I O0nM (a selective CCR3 agonist over this concentration range) containing 00 'Jy a concentration of a compound according to the Examples or solvent to the lower wells of the chemotaxis plate: The filter was then placed over the wells and 25 pl of eosinophil O suspension were added to the top of the filter. The plate was incubated for 1 hr at 370 C in a humidified incubator with a 95% air/5% CO 2 atmosphere to allow chemotaxis.
The medium, containing cells that had not migrated, was carefully aspirated from Sabove the filter and discarded. The filter was washed once with phosphate buffered saline 0 (PBS) containing 5 mM EDTA to remove any adherent cells. Cells that had migrated through the filter were pelleted by centrifugation (300xg for 5 mins at room temperature) 0 and the filter removed and the supernatant transferred to each well of a 96-well plate S 10 (Cos.tar). The pelleted cells were lysed by the addition of 28 Vl of PBS containing Triton x100 followed by two cycles of freeze/thawing. The cell lysate was then added to the supernatant. The number of eosinophils migrating was quantified according to the method of Strath et al.,J. Immunol. Methods, 1985, 83, 209 by measuring eosinophil peroxidase activity in the supernatant.
Compounds of the Examples were found to be antagonists of eotaxin mediated human eosinophil chemotaxis if the concentration response to eotaxin was shifted to the right of the control curve. Measuring the concentration of eotaxin required to give -chemotaxis in the presence or absence of compounds enables the apparent affinity of the compounds at CCR3 to be calculated, or the assay can be used to determine activity of compounds at a set concentration of compound against a predifined concentration of eotaxin.
Example Guinea-pig isolated trachea (See for example, Harrison, Carswell, H. Young, J.M. (1984) European J. Pharmacol., 106, 405-409.) Male albino Dunkin-Hartley guinea-pigs (250g) were killed by cervical dislocation and the whole trachea removed. After clearing the adherent connective tissue, the trachea was cut into six ring segments each three cartilage bands wide and then suspended in organ baths containing Krebs-Henseleit solution of the following composition NaCI 117.6, NaH 2
PO
4 0.9, NaHCO 3 25.0, MgSO 4 1.2, KCI 5.4, CaC1 2 2.6 and glucose 11.1. The buffer was maintained at 37 0 C and gassed with 5% CO 2 in oxygen. Indomethacin (2.8pM) was added to the Krebs solution to prevent development of smooth muscle tone due to the 00 070 cI 0 synthesis of cyclo-oxygenase products. The tracheal rings were suspended between two parallel tungsten wire hooks, one attached to an Ormed beam isometric force transducer and the other to a stationary support in the organ bath. Changes in isometric force were recorded on 2-channel Sekonic flat bed chart recorders.
00 5 Experimental protocols ,1 At the beginning of each experiment a force of Ig was applied to the tissues and 00 this was reinstated over a 60 minute equilibration period until a steady resting tone was Sachieved. Subsequently, a cumulative histamine concentration effect curve was constructed at 0.5 log 1 o unit increments, in each tissue. The tissues were then washed and approximately 30 minutes later, test compound or vehicle (20% DMSO) was added.
Following an incubation period of 60 minutes a second curve was performed to histamine.
Contraction responses were recorded as a percentage of the first curve maximum.
Data analysis Experimental curve data were analysed for the purposes of estimating the potencies (p[Aso] values) of histamine in the absence and presence of the test compound.
Affinity (pA 2 values of test compounds were subsequently calculated using the following equation: log(r-l) log[B] pA 2 where r= [Also in presence of test compound/[A]so in absence of antagonist and is the concentration of test compound. Compounds of the Examples were found to be HI antagonists.
Example 51 Histamine HI receptor binding activity of compounds of the invention was assessed by competition displacement of InM [3H]-pyrilamine (Amersham, Bucks, .Product code TRK 608, specific activity 30Ci/mmol) to 2tg membranes prepared from recombinant CHO-K1 cells expressing the human H1 receptor (Euroscreen SA, Brussels, Belgium, product code ES-390-M) in assay buffer (50mM Tris pH 7.4 containing 2mM MgC12, 250mM sucrose and 100mM NaCI) for 1 hour at room temperature.
The following compounds of the invention gave inhibition of [3H] pyrilimine binding: Example H1I pKi 6.9 8 7.8 6.9 14 6.9 16 7.6 18 6.7 24 7.7 7.8 27 6.6 28 7.4 31 6.8 37 6.7 39 6.9 42 6.9 44 7.9 7.2 As used herein, the term "comprise" and variations of the term, such as "comprising", "comprises" and "comprised", are not intended to exclude other additives, components, integers or steps.
Reference to any prior art in the specification is not, and should not be taken as, an acknowledgment, or any form of suggestion, that this prior art forms part of the common general knowledge in Australia or any other jurisdiction or that this prior art could reasonably be expected to be ascertained, understood and regarded as relevant by a person skilled in the art.

Claims (3)

  1. 2-oxo-thiazol-5-yl having a suitable electron withdrawing substituent in the 4- position; 2-oxo-oxazol-5-yl having a suitable electron withdrawing substituent in the 4- position; 005186984 74 00 S* 1H-1,2,3-triazol-4-yl having a suitable substituent in the O a* 4-oxo-lH-1,4-dihydropyridin-3-yl having a suitable electron withdrawing O substituent in the 2-position; 2,6-dioxo- H-1,2,3,6-tetrahydropyrimidin-4-yl having a suitable substituent in the
  2. 3-position and optionally substituted in one or more other ring positions;
  3. 6-oxo-lH-1,6-dihydropyridin-3-yl having a suitable electron withdrawing I substituent in the 2-position and/or the 5-position and optionally substituted in one oO or more other ring positions; 6-oxo-1H-l,6-dihydropyridin-3-yl having CH 2 CO 2 H on the ring nitrogen and 0 optionally substituted in one or more other ring positions; a CO 2 H, CH 2 CO2H or OCH 2 CO 2 H group on an optionally substituted phenyl, optionally substituted CH20phenyl or optionally substituted naphthyl ring; or, an NHS(0) 2 (C.4 alkyl) group on an optionally substituted aromatic heterocyclyl ring; or, where possible, a tautomer thereof. 13 A compound of formula (III) as claimed in claim 12 where R 3 is: 2-oxo-thiazol-5-yl having a suitable electron withdrawing substituent in the 4- position; 1H-1,2,3-triazol-4-yl having a suitable substituent in the 5-position; or, 6-oxo-lH-l,6-dihydropyridin-3-yl having Ci-4 fluoroalkyl or cyano in the 2- position or the 14 A compound of formula (III) as claimed in claim 13 wherein R 3 is: having CF 3 or C 2 Fs in the 4-position; 005186984 00 *0 1H-l,2,3-triazol-4-yl having CF 3 C 2 F 5 SCF 3 SCH 2 CF 3 or SC 2 F: (for example CF 3 or SCH 2 CF 3 in the 5-position; or, O 6-oxo-1H-1,6-dihydropyridin-3-yl having CF 3 or C 2 F 5 in the 2-position; or a pharmaceutically acceptable salt thereof. ID 00 5 15 A compound of formula (III) as claimed in claim 14 wherein R 3 is S having CF 3 or C 2 F 5 in the 4-position; or a pharmaceutically acceptable salt thereof. 00 16 A process for preparing a compound according to claim 4 which comprises reacting a O C compound of formula (IIIA) 0 HO I R 3 (IIA) with thionyl chloride or oxalyl chloride. 17 A process for preparing a compound of formula as defined in claim 1 which process comprises reacting a compound of formula (II): OH R1 O-C N-CH 2 CH 2 NH (II) H R wherein R' and R 2 are as defined in claim 1, with a compound of formula (IIIB): 0 L 1 R- 3 (III1B) wherein L' is a leaving group, and R 3 is a group that may be converted into a group R 3 and thereafter, converting said group R to a group R 3 18 A process according to claim 18 wherein R 3 is a 6-chloro-4-(trifluoromethyl)nicotin-3-yl group and is converted to a group R 3 which is -[(methylsulfonyl)amino]-4- (trifluoromethyl)nicotin-3-yl. 005186984 76 00 0 19 A compound of the formula or a pharmaceutically acceptable salt thereof, as defined O CN in claim 1, for use as an HI antagonist in the treatment of allergic disorders. C.) A compound of the formula or a pharmaceutically acceptable salt thereof, as defined in claim 1, for use in the treatment of obstructive diseases of airways including: chronic obstructive pulmonary disease (COPD); asthma; bronchitis; acute, allergic, atrophic rhinitis or V chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca 00 or rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous or CI pseudomembranous rhinitis or scrofulous rhinitis; seasonal rhinitis including rhinitis nervosa 00 0 (hay fever) or vasomotor rhinitis; sarcoidosis; farmer's lung, nasal polyposis; fibroid lung, O C 10 idiopathic interstitial pneumonia, antitussive activity, treatment of chronic cough associated with inflammatory conditions of the airways or iatrogenic induced cough. 21 A compound of formula or a pharmaceutically acceptable salt thereof as defined in claim 1 for use in the manufacture of a medicament for use in the treatment of allergic disorders. 22 A compound of formula or a pharmaceutically acceptable salt thereof as defined in claim 1 for use in the manufacture of a medicament for use in the treatment of chronic obstructive pulmonary disease (COPD); asthma; bronchitis; acute, allergic, atrophic rhinitis or chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous or pseudomembranous rhinitis or scrofulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) or vasomotor rhinitis; sarcoidosis; farmer's lung, nasal polyposis; fibroid lung, idiopathic interstitial pneumonia, antitussive activity, treatment of chronic cough associated with inflammatory conditions of the airways or iatrogenic induced cough.
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